5-membered heterocycle-based p38 kinase inhibitors

ABSTRACT

Provided are 5-membered heterocycle-based p38 kinase inhibitors. Further provided are pyrazole and imidazole-based p38 kinase, including p38α, and p38β kinase, inhibitors. Pharmaceutical compositions containing the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amelioration of one or more symptoms of p38 kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

RELATED APPLICATIONS

This application is Continuation Application of U.S. application Ser.No. 13/530,919 filed Jun. 22, 2012 which is a continuation of Ser. No.12/950,649 filed Nov. 19, 2010 which is a Divisional Application of U.S.application Ser. No. 10/877,534 filed Jun. 25, 2004 which claims benefitunder 35 U.S.C. §119(e) of U.S. Provisional Application Nos. 60/560,481,filed Apr. 7, 2004, 60/499,054, filed Aug. 29, 2003, and 60/483,428filed Jun. 26, 2003, the contents of which are incorporated herein byreference in their entirety.

Priority is claimed herein under 35 U.S.C. §119(e) to U.S. ProvisionalPatent Application Nos. 60/483,428, 60/499,054 and 60/560,481, filedJun. 26, 2003, Aug. 29, 2003 and Apr. 7, 2004, respectively; andentitled “PYRAZOLE-BASED p38 INHIBITORS,” “5-MEMBERED HETEROCYCLE-BASEDp38 KINASE INHIBITORS,” and “5-MEMBERED HETEROCYCLE-BASED p38 KINASEINHIBITORS,” respectively. The disclosures of the above-referencedapplications are incorporated by reference herein in their entirety.

FIELD

Provided herein are 5-membered heterocycle-, including pyrazole- andimidazole-, based compounds which have cytokine inhibitory activity.Also provided are uses of the compounds for treating conditionsassociated with p38α and β kinases and for treating p38kinase-associated conditions.

BACKGROUND

A large number of cytokines participate in the inflammatory response,including IL-1, IL6, IL-8 and TNF-α. Overproduction of cytokines such asIL-1 and TNF-α are implicated in a wide variety of diseases, includinginflammatory bowel disease, rheumatoid arthritis, psoriasis, multiplesclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, andcongestive heart failure, among others (Henry et al., Drugs Fut.24:1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6:807-823(1999)). Evidence in human patients indicates that protein antagonistsof cytokines are effective in treating chronic inflammatory diseases,such as, for example, a monoclonal antibody to TNF-α (Remicade) (Rankinet al., Br. J. Rheumatol., 34:334-342 (1995)), and a soluble TNF-αreceptor-Fc fusion protein (Etanercept) (Moreland et al., 25 Ann.Intern. Med., 130:478-486 (1999)).

The biosynthesis of TNF-α occurs in many cell types in response to anexternal stimulus, such as, for example, a mitogen, an infectiousorganism, or trauma. Important mediators of TNF-α production are themitogen-activated protein (MAP) kinases, and in particular, p38 kinases.These kinases are activated in response to various stress stimuli,including but not limited to proinflammatory cytokines, endotoxin,ultraviolet light, and osmotic shock. Activation of p38 requires dualphosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) onthreonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38isozymes.

There are four known isoforms of p38, i.e., p38α, p38β, p38γ, and p38δ.The α and β isoforms are expressed in inflammatory cells and are keymodulators of TNF-α production. Inhibiting the p38α and β enzymes incells results in reduced levels of TNF-α expression. Also, administeringinhibitors of p38α and β in animal models of inflammatory disease hasproven that such inhibitors are effective in treating those diseases.Accordingly, the p38 enzymes serve an important role in inflammatoryprocesses mediated by IL-1 and TNF-α. See, e.g., U.S. Pat. Nos.6,277,989, 6,130,235, 6,147,080, 5,945,418, 6,251,914, 5,977,103,5,658,903, 5,932,576, and 6,087,496; and in International PatentApplication Publication Nos. WO 00/56738, WO 01/27089, WO 01/34605, WO00/12497, WO 00/56738, WO 00/12497 and WO 00/12074. See also, U.S. Pat.Nos. 6,376,527; 6,316,466 and 6,444,696; and International PatentApplication Publication Nos. WO 99/57101, WO 02/40486, WO 03/032970, WO03/033482, WO 03/032971, WO 03/032986, WO 03/032980, WO 03/032987, WO03/033483, WO 03/033457 and WO 03/032972.

Thus, there is a need for inhibitors of p38 kinases, including p38α andp38b kinase, for treatment, prevention, or amelioration of one or moresymptoms of diseases and disorders associated with p38 kinase activity.

SUMMARY

Provided herein are compounds, compositions and methods of treating,preventing, or ameliorating one or more symptoms of conditionsassociated with p38 kinase activity. In one embodiment, the compoundsfor use in the compositions and methods are pyrazole- or imidazole-basedcompounds. In another embodiment, the pyrazole- or imidazole-basedcompounds are useful as kinase inhibitors, including p38α and p38βkinases.

In one embodiment, the compounds provided herein have the formula:

or a pharmaceutically acceptable derivative thereof, where:

R¹ is hydrogen, acyl or —P(O)(OH)₂;

R² is hydrogen, halo, optionally substituted alkyl, alkylthio,alkylsulfinyl, alkylsulfonyl, optionally substituted alkoxy, optionallysubstituted heterocyclyloxy or alkylamino;

G is an aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl or aheterocyclyl ring optionally fused to a phenyl ring, and is substitutedwith R³ and R⁴, provided that the heterocyclyl ring is attached to thecarbonyl group via a carbon ring atom, or G is OR⁸³ or NR⁸⁰R⁸¹;

B is an aryl or heteroaryl ring;

C is a 5-membered heteroaryl ring containing one or two heteroatoms inthe ring;

D is heteroaryl, optionally substituted heteroaryl or —C(O)NR⁸⁰R⁸¹;

each R⁸⁰ and R⁸¹ is independently hydrogen, alkyl, cycloalkyl, alkoxy,hydroxy, heteroaryl or optionally substituted heteroaryl;

R⁸³ is hydrogen, alkyl, cycloalkyl, heteroaryl or optionally substitutedheteroaryl;

R³ is selected from the group consisting of:

(a) amino, alkylamino or dialkylamino;

(b) acylamino;

(c) optionally substituted heterocyclyl;

(d) optionally substituted aryl or heteroaryl;

(e) heteroalkyl;

(f) heteroalkenyl;

(g) heteroalkynyl;

(h) heteroalkoxy;

(i) heteroalkylamino;

(j) optionally substituted heterocyclylalkyl;

(k) optionally substituted heterocyclylalkenyl;

(l) optionally substituted heterocyclylalkynyl;

(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;

(n) optionally substituted heterocyclylalkylamino;

(o) optionally substituted heterocyclylalkylcarbonyl;

(p) heteroalkylcarbonyl;

(q) —NHSO₂R⁶ where R⁶ is alkyl, heteroalkyl or optionally substitutedheterocyclylalkyl;

(r) —NHSO₂NR⁷R⁸ where R⁷ and R⁸ are, independently of each other,hydrogen, alkyl or heteroalkyl;

(s) —Y-(alkylene)-R⁹ where: Y is a single bond, —O—, —NH— or —S(O)_(n)—(where n is an integer from 0 to 2); and R⁹ is halo, cyano, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, —COOH, —COR¹⁰, —COOR¹¹, —CONR¹²R¹³, —SO₂R¹⁴,—SO₂NR¹⁵R¹⁶, —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹, where R¹⁰ is alkyl oroptionally substituted heterocycle, R¹¹ is alkyl, and R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are, independently of each other, hydrogen,alkyl or heteroalkyl;

(t) —C(═NR²⁰)(NR²¹R²²) where R²⁰, R²¹ and R²² independently representhydrogen, alkyl or hydroxy, or R²⁰ and R²¹ together are —(CH₂)_(n)—where n is 2 or 3 and R²² is hydrogen or alkyl;

(u) —NHC(X)NR²³R²⁴ where X is —O— or —S—, and R²³ and R²⁴ are,independently of each other, hydrogen, alkyl or heteroalkyl;

(v) —CONR²⁵R²⁶ where R²⁵ and R²⁶ independently represent hydrogen,alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R²⁵and R²⁶ together with the nitrogen to which they are attached form anoptionally substituted heterocyclyl ring;

(w) —S(O)_(n)R²⁷ where n is an integer from 0 to 2, and R²⁷ is alkyl,heteroalkyl, optionally substituted heterocyclylalkyl or —NR²⁸R²⁹ whereR²⁸ and R²⁹ are, independently of each other, hydrogen, alkyl orheteroalkyl;

(x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, alloptionally substituted with alkyl, halo, hydroxy or amino;

(y) arylaminoalkylene or heteroarylaminoalkylene;

(z) Z-alkylene-NR³⁰R³¹ or Z-alkylene-OR³² where Z is —NH—, —N(loweralkyl)- or —O—, and R³⁰, R³¹ and R³² are independently of each other,hydrogen, alkyl or heteroalkyl;

(aa) —OC(O)-alkylene-CO₂H or —OC(O)—NR′R″ (where R′ and R″ areindependently hydrogen or alkyl);

(bb) heteroarylalkenylene or heteroarylalkynylene;

(cc) hydrogen;

(dd) halo;

(ee) pseudohalo;

(ff) hydroxy;

(gg) optionally substituted alkoxy;

(hh) C(L)R⁴⁰, where L is O, S or NR⁵⁵; R⁴⁰ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heteroarylium, optionally substitutedcycloalkyl, optionally substituted heterocyclyl, C(L)R⁵⁶, halopseudohalo, OR⁵⁵, SR⁵⁵, NR⁵⁷R⁵⁸ or SiR⁵²R⁵³R⁵⁴; where R⁵², R⁵³ and R⁵⁴are selected as in (i) or (ii) as follows (i) R⁵², R⁵³ and R⁵⁴ are eachindependently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵ or NR⁶²R⁶³; or (ii) anytwo of R⁵², R⁵³ and R⁵⁴ together form alkylene, alkenylene, alkynylene,heteroalkylene; and the other is selected as in (i); R⁵⁵ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl orheterocyclyl; R⁵⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵ or NR⁶⁴R⁶⁵;where R⁶⁴ and R⁶⁵ are each independently hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁶⁶or NR⁶²R⁶³, or R⁶⁴ and R⁶⁵ together form alkylene, alkenylene,alkynylene, heteroalkylene, where R⁶⁶ is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl;R⁵⁷ and R⁵⁸ are selected as in (i) or (ii) as follows (i) R⁵⁷ and R⁵⁸are each independently hydrogen, optionally substituted alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl,OR⁵⁵, NR⁶⁷R⁶⁸ or C(L)R⁶⁹, where R⁶⁷ and R⁶⁸ are each independentlyhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium,cycloalkyl or heterocyclyl, or together form alkylene, alkenylene,alkynylene, heteroalkylene; and R⁶⁹ is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁷⁰or NR⁶²R⁶³, where R⁷⁰ is alkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroarylium, cycloalkyl, heterocyclyl; or (ii) R⁵⁷ and R⁵⁸ togetherform alkylene, alkenylene, alkynylene, heteroalkylenem oralkylenoxyalkylene; R⁶² and R⁶³ are each independently hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl,heterocyclyl, or R⁶² and R⁶³ together form alkylene, alkenylene,alkynylene, heteroalkylene; and

(ii) optionally substituted alkyl;

R⁴ is selected from the group consisting of:

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) alkoxy; and

(e) hydroxy;

R⁵ is selected from the group consisting of

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) haloalkyl;

(e) thioalkyl;

(f) hydroxy;

(g) amino;

(h) alkylamino;

(i) dialkylamino;

(j) heteroalkyl;

(k) optionally substituted heterocycle;

(l) optionally substituted heterocyclylalkyl;

(m) optionally substituted heterocyclylalkoxy;

(n) alkylsulfonyl;

(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylaminosulfonyl;

(p) heteroalkoxy; and

(q) carboxy;

R⁶ is selected from the group consisting of:

(a) hydrogen;

(b) halo;

(c) alkyl; and

(d) alkoxy.

Also provided herein are pharmaceutical compositions containing acompound provided herein in combination with a pharmaceuticallyacceptable carrier.

Methods of treating, preventing or ameliorating one or more symptoms ofcytokine mediated disease in a mammal, by administering to a mammalianpatient, in need of such treatment, a compound of formula I areprovided. Diseases and disorders treated, prevented, or whose symptomsare ameliorated, include, but are not limited to, chronic inflammatorydiseases, inflammatory bowel disease, rheumatoid arthritis, psoriasis,multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,and congestive heart failure.

Methods of preventing or inhibiting inflammatory responses using thecompounds and compositions provided herein are also provided.

Further provided are methods of inhibiting p38 kinases, including p38αand p38β kinases, using the compounds and compositions provided herein.

Articles of manufacture are provided containing packaging material, acompound or composition provided herein which is useful for treating,preventing, or ameliorating one or more symptoms of p38 kinase-mediateddiseases or disorders, and a label that indicates that the compound orcomposition is useful for treating, preventing, or ameliorating one ormore symptoms of p38 kinase-mediated diseases or disorders.

DETAILED DESCRIPTION A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the invention(s) belong. All patents, patent applications,published applications and publications, Genbank sequences, databases,websites and other published materials referred to throughout the entiredisclosure herein, unless noted otherwise, are incorporated by referencein their entirety. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Wherereference is made to a URL or other such identifier or address, itunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

As used herein, p38α refers to the enzyme disclosed in Han et al. (1995)Biochim. Biophys. Acta 1265(2-3):224-7. As used herein, p38β refers tothe enzyme disclosed in Jiang et al. (1996) J. Biol. Chem.271(30):17920-6. As used herein, p38γ refers to the enzyme disclosed inLi et al. (1996) Biochem. Biophys. Res. Commun. 228: 334-340. As usedherein, p38δ refers to the enzyme disclosed in Wang et al. (1997) J.Biol. Chem. 272(38):23668-74.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydratesor prodrugs thereof. Such derivatives may be readily prepared by thoseof skill in this art using known methods for such derivatization. Thecompounds produced may be administered to animals or humans withoutsubstantial toxic effects and either are pharmaceutically active or areprodrugs. Pharmaceutically acceptable salts include, but are not limitedto, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, nitrates, borates, methanesulfonates, benzenesulfonates,toluenesulfonates, salts of mineral acids, such as but not limited tohydrochlorides, hydrobromides, hydroiodides and sulfates; and salts oforganic acids, such as but not limited to acetates, trifluoroacetates,oxalates, benzoates, salicylates, maleates, lactates, malates,tartrates, citrates, ascorbates, succinates, butyrates, valerates andfumarates. In addition, zwitterions (“inner salts”) may be formed. Incertain embodiments, salt forms of the compounds improve the compounds'dissolution rate and oral bioavailability. Pharmaceutically acceptableesters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl estersof acidic groups, including, but not limited to, carboxylic acids,phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids andboronic acids. Pharmaceutically acceptable enol ethers include, but arenot limited to, derivatives of formula C═C(OR) where R is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl or heterocyclyl. Pharmaceutically acceptable enol estersinclude, but are not limited to, derivatives of formula C═C(OC(O)R)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptablesolvates and hydrates are complexes of a compound with one or moresolvent or water molecules, or 1 to about 100, or 1 to about 10, or oneto about 2, 3 or 4, solvent or water molecules.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, pentyl, and the like.

The term “cycloalkyl” refers to a saturated or partially unsaturatednonaromatic cyclic hydrocarbon ring system, preferably containing 1 to 3rings and 3 to 7 carbons per ring which may be further fused with anunsaturated C₃-C₇ carbocylic ring. Exemplary groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl,cyclododecyl, and adamantyl. A “substituted cycloalkyl” is substitutedwith one or more alkyl or substituted alkyl groups as described above,or one or more groups described above as alkyl substituents. Theexpression “lower cycloalkyl” refers to an unsubstituted saturated orunsaturated nonaromatic cyclic hydrocarbon ring system containing 3 to 5carbon atoms.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene, propylene,2-methylpropylene, pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkenylene” means a linear divalent hydrocarbon radical of two to sixcarbon atoms or a branched divalent hydrocarbon radical of three to sixcarbon atoms, containing at least one double bond, e.g., ethenylene,propenylene, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched divalent hydrocarbon radical of three to sixcarbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkynylene” means a linear divalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynylene,propynylene, and the like.

“Alkoxy” means a radical —OR where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, 2-propoxy, the like.

“Acyl” means a radical —C(O)R where R is alkyl or haloalkyl e.g.,acetyl, trifluoroacetyl, and the like.

“Acylamino” means a radical —NRC(O)R′ where R is hydrogen or alkyl, andR′ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl,e.g., acetylamino, 2-amino-2-methylpropionamide, and the like.

“Halo” means fluoro, chloro, bromo, or iodo, generally fluoro andchloro.

“Haloalkyl” means alkyl substituted with one or more same or differenthalo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, andthe like. The aryl ring may optionally be fused to a 5-, 6- or7-membered monocyclic saturated ring optionally containing 1 or 2heteroatoms independently selected from oxygen, nitrogen or sulfur, theremaining ring atoms being C where one or two C atoms are optionallyreplaced by a carbonyl group. Representative aryl radicals with fusedrings include, but are not limited to, 2,3-dihydrobenzo[1,4]dioxan,chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran,benzo[1,3]dioxole, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4tetrahydroquinoline, 2,3-dihydro-1H-indole,2,3-dihydro-1H-isoindole, benzimidazol-2-one, 3H-benzoxazol-2-one, andthe like.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms containing one, two, or three ring heteroatomsselected from N, O, or S, the remaining ring atoms being C. The termalso includes those radicals where a heteroatom within the ring has beenoxidized or quaternized, such as, for example, to form an N-oxide or aquaternary salt. Representative examples include, but are not limitedto, thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl,isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl,pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl,pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, and theircorresponding N-oxides, (e.g. pyridyl N-oxide, quinolinyl N-oxide),their quaternary salts and the like.

“Heterocycle” or “heterocyclyl” means a cyclic nonaromatic radical of 3to 8 ring atoms in which one or two ring atoms are heteroatoms selectedfrom N, O, or S(O)_(n), (where n is an integer from 0 to 2), theremaining ring atoms being C where one or two C atoms are optionallyreplaced by a carbonyl group. The term also includes those radicalswhere a ring nitrogen atom has been oxidized or quaternized, such as,for example, to form an N-oxide or a quaternary salt. Representativeexamples include, but are not limited to, tetrahydropyranyl,tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino,piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl,2,2-dimethyl-1,3-dioxalanyl, sulfolanyl, 2-oxazolidonyl,2-imidazolidonyl, S,S-dioxo-thiomorpholino, and the like.

“Heterocycloamino” means a saturated monovalent cyclic group of 4 to 8ring atoms, wherein at least one ring atom is N and optionally containsone additional ring atom selected from N or O, the remaining ring atomsbeing C. The term includes groups such as pyrrolidino, piperidino,morpholino, piperazino and the like.

“Optionally substituted alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl”means an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl group, as definedherein, which is optionally substituted independently with one or twosubstituents selected from alkyl, phenyl, benzyl, haloalkyl,heteroalkyl, halo, cyano, heterocyclyl, acyl, —OR (where R is hydrogenor alkyl), —NRR′ (where R and R′ are independently selected fromhydrogen, acyl, or alkyl which is optionally substituted with hydroxy,alkoxy, cyano, halo or heterocyclyl), —NHCOR (where R is alkyl which isoptionally substituted with hydroxy, alkoxy, cyano, halo orheterocyclyl), —NRS(O)_(n)R′ (where R is hydrogen or alkyl, n is aninteger from 0 to 2; and R′ is hydrogen, alkyl or heteroalkyl, and isoptionally substituted with hydroxy, alkoxy, cyano, halo orheterocyclyl), —NRS(O)_(n)NR′R″ (where R is hydrogen or alkyl, n is aninteger from 0 to 2; and R′ and R″ are independently hydrogen, alkyl orheteroalkyl and are optionally substituted with hydroxy, alkoxy, cyano,halo or heterocyclyl), —S(O)_(n)R (where n is an integer from 0 to 2;and R is hydrogen, alkyl or heteroalkyl and is optionally substitutedwith hydroxy, alkoxy, cyano, halo or heterocyclyl), —S(O)_(n)NRR′ (wheren is an integer from 0 to 2; and R and R′ are independently hydrogen,alkyl or heteroalkyl and are optionally substituted with hydroxy,alkoxy, cyano, halo or heterocyclyl), —COOR, -(alkylene)COOR (where R ishydrogen or alkyl), —CONR′R″ or -(alkylene)CONR′R″ (where R′ and R″ areindependently hydrogen or alkyl, or together form a heterocyclyl ringwith the nitrogen atom to which they are attached).

“Optionally substituted aryl, heteroaryl or heterocyclyl” means an aryl,heteroaryl or heterocyclyl ring as defined above, which is optionallysubstituted independently with one or two substituents selected fromalkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, acyl, —OR(where R is hydrogen or alkyl), —NRR′ (where R and R′ are independentlyselected from hydrogen, alkyl or acyl), —NHCOR (where R is alkyl),—NRS(O)_(n)R′ (where R is hydrogen or alkyl, n is an integer from 0 to 2and R′ is hydrogen, alkyl or heteroalkyl), —NRS(O)_(n)NR′R″ (where R ishydrogen or alkyl, n is an integer from 0 to 2 and R′ and R″ areindependently hydrogen, alkyl or heteroalkyl), —S(O)_(n)R (where n is aninteger from 0 to 2 and R is hydrogen, alkyl or heteroalkyl),—S(O)_(n)NRR′ (where n is an integer from 0 to 2 and R and R′ areindependently hydrogen, alkyl or heteroalkyl), —COOR, -(alkylene)COOR(where R is hydrogen or alkyl), —CONR′R″ or -(alkylene)CONR′R″ (where R′and R″ are independently hydrogen or alkyl).

“Heteroalkyl” means an alkyl radical as defined above, carrying one, twoor three substituents selected from —NR^(a)R^(b), —OR^(c) wherein R^(a),R^(b) and R^(c) are independently of each other hydrogen, alkyl or acyl,or R^(a) and R^(b) together form heterocycloamino group. Representativeexamples include, but are not limited to, hydroxymethyl, acetoxymethyl,3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl,2-dimethylaminoethyl, 2-acetylaminoethyl, 3-[pyrrolidin-1-yl]ethyl andthe like.

“Heteroalkenyl” means an alkenyl radical as defined above, carrying oneor two substituents selected from —NR^(a)R^(b), —OR^(c) or—S(O)_(n)R^(d) wherein R^(a), R^(b) and R^(c) are independently of eachother hydrogen or alkyl, and R^(d) is alkyl or —NRR′ (where R and R′ areindependently of each other hydrogen or alkyl. Representative examplesinclude, but are not limited to, 3-hydroxy-1-propenyl,3-aminoprop-1-enyl, 2-aminosulfonylethenyl, 2-methylsulfonylethenyl, andthe like.

“Heteroalkynyl” means an alkynyl radical as defined above, carrying oneor two substituents selected —NR^(a)R^(b), —OR^(c), —S(O)_(n)R^(d) or—S(O)_(n)NRR (where R and R′ are independently of each other hydrogen oralkyl) wherein R^(a), R^(b) and R^(c) are independently of each otherhydrogen or alkyl, and R^(d) is alkyl and n is an integer from zero totwo. Representative examples include, but are not limited to,3-hydroxy-1-propynyl, 3-dimethylaminoprop-1-ynyl and the like.

“Heteroalkoxy” means a radical —OR where R is heteroalkyl group asdefined above, e.g., 2-hydroxyethoxy, 3-hydroxypropoxy,2,3-dihydroxypropoxy, 2-aminoethoxy, and the like.

“Heteroalkylamino” means a radical —NR^(a)R^(b) where R^(a) is hydrogenor alkyl, and R^(b) is a heteroalkyl group as defined above, e.g.,2-hydroxyethylamino, 3-dimethylaminopropylamino, and the like.

“Optionally substituted heterocyclylalkyl” means a radical —R^(a)R^(b)where R^(a) is an alkylene group, and R^(b) is an optionally substitutedheterocyclyl group as defined above e.g., 2-(morpholin-4-yl)ethyl,3(piperidin-1-yl)-2-methylpropyl, and the like.

“Optionally substituted heterocyclylalkenyl” means a radical —R^(a)R^(b)where R^(a) is an alkenylene group and R^(b) is an optionallysubstituted heterocyclyl group as defined above e.g.,3-(morpholin-4-yl)prop-1-enyll, 3-(piperidin-1-yl)prop-1-enyl,3-(4-methylpiperazin-1-yl)prop-1-enyl, and the like.

“Optionally substituted heterocyclylalkynyl” means a radical —R^(a)R^(b)where R^(a) is an alkynyl group and R^(b) is an optionally substitutedheterocyclyl group as defined above e.g., 3-(morpholin-4-yl)prop-1-ynyl,3-(piperidin-1-yl)prop-1-ynyl, and the like.

“Optionally substituted heterocyclylalkoxy” means a radical —OR where Ris an optionally substituted heterocyclylalkyl group as defined above,e.g., 2-(morpholin-4-yl)-ethoxy, 3-(piperazin-1-yl)propoxy,2-[2-oxopyrrolidin-1-yl]ethoxy, and the like.

“Optionally substituted heterocyclylalkylamino” means a radical—NR^(a)R^(b) where R^(a) is hydrogen or alkyl and R^(b) is an optionallysubstituted heterocyclylalkyl group as defined above, e.g.,2-(pyrrolidin-2-yl)ethylamino, 3-(piperidin-1-yl)propylamino, and thelike.

“Optionally substituted heteroaralkyloxy means a radical —O—R^(a) whereR^(a) is a heteroaralkyl radical e.g. 2-(pyridin-3-yl)ethoxy,2-[3(2H)-pyridazon-1-yl]ethoxy and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “aryl group optionally mono- ordi-substituted with an alkyl group” means that the alkyl may but neednot be present, and the description includes situations where the arylgroup is mono- or disubstituted with an alkyl group and situations wherethe heterocyclo group is not substituted with the alkyl group.

“Amino protecting group” refers to those organic groups intended toprotect nitrogen atoms against undesirable reactions during syntheticprocedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl(Boc), trifluoroacetyl, and the like.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds. It is also understood that the chemical groups, as describedherein, can be substituted or unsubstituted, branched or unbranched, asappropriate and desired.

All stereoisomers of the compounds provided herein are contemplated,either in admixture or in pure or substantially pure form. Thedefinition of compounds provided herein embraces all the possiblestereoisomers and their mixtures. It embraces the racemic forms and theisolated optical isomers having the specified activity. The racemicforms can be resolved by physical methods, such as, for example,fractional crystallization, separation or crystallization ofdiastereomeric derivatives or separation by chiral columnchromatography. The individual optical isomers can be obtained from theracemates from the conventional methods, such as, for example, saltformation with an optically active acid followed by crystallization.

The compounds provided herein may also have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent is aprodrug. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see, e.g.:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Acamedic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsenand H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H.Bundgaard, p. 113-191 (1991); and

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), each ofwhich is incorporated herein by reference.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compounds and compositions herein, such as use for treating p38kinase mediated diseases or disorders, or diseases or disorders in whichp38 kinase activity, including p38α and p38β kinase activity, isimplicated.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

As used herein, IC₅₀ refers to an amount, concentration or dosage of aparticular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of p38α kinase activity, in an assay thatmeasures such response.

B. Compounds

The compounds provided herein for use in the compositions and methodsare active in assays that measure p38 kinase activity, including, butnot limited to, p38α and p38β kinase activity. In one embodiment, thecompounds provided herein have formulae I:

or a pharmaceutically acceptable derivative thereof, where:

R¹ is hydrogen, acyl or —P(O)(OH)₂;

R² is hydrogen, halo, alkyl or alkylthio;

A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to aphenyl ring, provided that the heterocyclyl ring is attached to thecarbonyl group via a carbon ring atom;

B is an aryl or heteroaryl ring;

C is a 5-membered heteroaryl ring containing one or two heteroatoms inthe ring;

D is heteroaryl, optionally substituted heteroaryl or —C(O)NR⁸⁰R⁸¹,where R⁸⁰ and R⁸¹ are independently hydrogen, alkyl, cycloalkyl, alkoxy,hydroxy, heteroaryl or optionally substituted heteroaryl;

R³ is selected from the group consisting of:

(a) amino, alkylamino or dialkylamino;

(b) acylamino;

(c) optionally substituted heterocyclyl;

(d) optionally substituted aryl or heteroaryl;

(e) heteroalkyl;

(f) heteroalkenyl;

(g) heteroalkynyl;

(h) heteroalkoxy;

(i) heteroalkylamino;

(j) optionally substituted heterocyclylalkyl;

(k) optionally substituted heterocyclylalkenyl;

(l) optionally substituted heterocyclylalkynyl;

(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;

(n) optionally substituted heterocyclylalkylamino;

(o) optionally substituted heterocyclylalkylcarbonyl;

(p) heteroalkylcarbonyl;

(q) —NHSO₂R⁶ where R⁶ is alkyl, heteroalkyl or optionally substitutedheterocyclylalkyl;

(r) —NHSO₂NR⁷R⁸ where R⁷ and R⁸ are, independently of each other,hydrogen, alkyl or heteroalkyl;

(s) —Y-(alkylene)-R⁹ where: Y is a single bond, —O—, —NH— or —S(O)_(n)—(where n is an integer from 0 to 2); and R⁹ is halo, cyano, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, —COOH, —COR¹⁰, —COOR¹¹, CONR¹²R¹³, —SO₂R¹⁴,—SO₂NR¹⁵R¹⁶, —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹, where R¹⁰ is alkyl oroptionally substituted heterocycle, R¹¹ is alkyl, and R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are, independently of each other, hydrogen,alkyl or heteroalkyl;

(u) —C(═NR²⁰)(NR²¹R²²) where R²⁰, R²¹ and independently representhydrogen, alkyl or hydroxy, or R²⁰ and R²¹ together are —(CH₂)_(n)—where n is 2 or 3 and R²² is hydrogen or alkyl;

(u) —NHC(X)NR²³R²⁴ where X is —O— or —S—, and R²³ and R²⁴ are,independently of each other, hydrogen, alkyl or heteroalkyl;

(v) —CONR²⁵R²⁶ where R²⁵ and R²⁶ independently represent hydrogen,alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R²⁵and R²⁶ together with the nitrogen to which they are attached form anoptionally substituted heterocyclyl ring;

(w) —S(O)_(n)R²⁷ where n is an integer from 0 to 2, and R²⁷ is alkyl,heteroalkyl, optionally substituted heterocyclylalkyl or —NR²⁸R²⁹ whereR²⁸ and R²⁹ are, independently of each other, hydrogen, alkyl orheteroalkyl;

(x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, alloptionally substituted with alkyl, halo, hydroxy or amino;

(y) arylaminoalkylene or heteroarylaminoalkylene;

(z) Z-alkylene-NR³⁰R³¹ or Z-alkylene-OR³² where Z is —NH—, —N(loweralkyl)- or —O—, and R³⁰, R³¹ and R³² are independently of each other,hydrogen, alkyl or heteroalkyl;

(aa) —OC(O)-alkylene-CO₂H or —OC(O)—NR′R″ (where R′ and R″ areindependently hydrogen or alkyl);

(bb) heteroarylalkenylene or heteroarylalkynylene;

(cc) hydrogen;

(dd) halo;

(ee) pseudohalo;

(ff) hydroxy;

(gg) optionally substituted alkoxy;

(hh) C(L)R⁴⁰, where L is O, S or NR⁵⁵; R⁴⁰ is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heteroarylium, optionally substitutedcycloalkyl, optionally substituted heterocyclyl, C(L)R⁵⁶, halopseudohalo, OR⁵⁵, SR⁵⁵, NR⁵⁷R⁵⁸ or SiR⁵²R⁵³R⁵⁴; where R⁵², R⁵³ and R⁵⁴are selected as in (i) or (ii) as follows (i) R⁵², R⁵³ and R⁵⁴ are eachindependently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵ or NR⁶²R⁶³; or (ii) anytwo of R⁵², R⁵³ and R⁵⁴ together form alkylene, alkenylene, alkynylene,heteroalkylene; and the other is selected as in (i); R⁵⁵ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl orheterocyclyl; R⁵⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵ or NR⁶⁴R⁶⁵;where R⁶⁴ and R⁶⁵ are each independently hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁶⁶or NR⁶²R⁶³, or R⁶⁴ and R⁶⁵ together form alkylene, alkenylene,alkynylene, heteroalkylene, where R⁶⁶ is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl;R⁵⁷ and R⁵⁸ are selected as in (i) or (ii) as follows (i) R⁵⁷ and R⁵⁸are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵, NR⁶⁷R⁶⁸ orC(L)R⁶⁹, where R⁶⁷ and R⁶⁸ are each independently hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl orheterocyclyl, or together form alkylene, alkenylene, alkynylene,heteroalkylene; and R⁶⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁷⁰ or NR⁶²R⁶³,where R⁷⁰ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium,cycloalkyl, heterocyclyl; or (ii) R⁵⁷ and R⁵⁸ together form alkylene,alkenylene, alkynylene, heteroalkylene; R⁶² and R⁶³ are eachindependently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroarylium, cycloalkyl, heterocyclyl, or R⁶² and R⁶³ together formalkylene, alkenylene, alkynylene, heteroalkylene; and

(ii) optionally substituted alkyl;

R⁴ is selected from the group consisting of:

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) alkoxy; and

(e) hydroxy;

R⁵ is selected from the group consisting of

(a) hydrogen;

(b) halo;

(c) alkyl;

(d) haloalkyl;

(e) thioalkyl;

(f) hydroxy;

(g) amino;

(h) alkylamino;

(i) dialkylamino;

(j) heteroalkyl;

(k) optionally substituted heterocycle;

(l) optionally substituted heterocyclylalkyl;

(m) optionally substituted heterocyclylalkoxy;

(n) alkylsulfonyl;

(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylaminosulfonyl;

(p) heteroalkoxy; and

(q) carboxy;

R⁶ is selected from the group consisting of:

(a) hydrogen;

(b) halo;

(c) alkyl; and

(d) alkoxy.

In one embodiment, C is a 5-membered heteroaryl ring containing one ortwo heteroatoms in the ring. In another embodiment, C is selected frompyrazole, imidazole, pyrrole, thiazole, isothiazole, oxazole, isoxazole,furan and thiophene rings. In another embodiment, C is a pyrazole orimidazole ring. In another embodiment, C is an imidazole ring. Inanother embodiment, C is a pyrazole ring.

1. Pyrazole-Based Compounds

In one embodiment, C is a pyrazole ring and the compounds providedherein have formulae II:

or a pharmaceutically acceptable derivative thereof, where the variablesare as defined elsewhere herein. In this embodiment, the hydrogen of thering NH group may be replaced by one of the substituents shown in thestructure (i.e., —C(O)-A(R³)(R⁴), —R², or —B(D)(R⁶)(R⁵)).

In another embodiment, the compounds provided herein have formulae III:

or a pharmaceutically acceptable derivative thereof, where the variablesare as defined elsewhere herein.

In another embodiment, the compounds provided herein have formulae IV:

or a pharmaceutically acceptable derivative thereof, where the variablesare as defined elsewhere herein.

In another embodiment, the compounds provided herein have formulae V:

or a pharmaceutically acceptable derivative thereof, where the variablesare as defined elsewhere herein.

In another embodiment, the compounds provided herein have formulae Va:

or a pharmaceutically acceptable derivative thereof, wherein A, D, R³,R⁴, and R⁶ are as defined elsewhere herein.

2. Imidazole-Based Compounds

In another embodiment, the compounds are imidazole-based compounds offormulae VI:

or a pharmaceutically acceptable derivative thereof, where the variablesare as defined elsewhere herein. In this embodiment, the hydrogen of thering NH group may be replaced by one of the substituents shown in thestructure structure (i.e., —C(O)-A(R³)(R⁴), —R², or —B(D)(R⁶)(R⁵).

In another embodiment, the compounds provided herein have formulae VII:

or a pharmaceutically acceptable derivative thereof, where the variablesare as defined elsewhere herein.

In another embodiment, the compounds provided herein have formulae VIM

or a pharmaceutically acceptable derivative thereof, where the variablesare as defined elsewhere herein.

3. Other embodiments

In other embodiments, the compounds for use in the compositions andmethods provided herein have the above formulae, or pharmaceuticallyacceptable derivatives thereof, where R¹ is hydrogen. In anotherembodiment, R² is hydrogen or lower alkyl. In another embodiment, R² ishydrogen.

In another embodiment, G is OR⁸³ or NR⁸⁰R⁸¹. In another embodiment, R⁸³is alkyl or cycloalkyl. In another embodiment, R⁸³ is alkyl. In anotherembodiment, R⁸³ is ethyl. In another embodiment, R⁸⁰ and R⁸¹ are eachindependently hydrogen, alkyl or cycloalkyl. In another embodiment, R⁸⁰and R⁸¹ are each independently hydrogen or cycloalkyl. In anotherembodiment, R⁸⁰ and R⁸¹ are each independently hydrogen or cyclohexyl.In another embodiment, G is NH₂ or NH(cyclohexyl).

In another embodiment, G is aryl, heteroaryl, cycloalkyl, heterocyclylor heterocyclyl optionally fused to phenyl, and is substituted with R³and R⁴, provided that the heterocyclyl ring is attached to the carbonylgroup via a carbon ring atom. In another embodiment, G is phenyl,cyclohexyl, cyclopentyl or benzyl, and is substituted with R³ and R⁴. Inanother embodiment, G is phenyl and is substituted with R³ and R⁴.

In another embodiment, A is an aryl ring. In another embodiment, A is aphenyl ring.

In another embodiment, B is an aryl ring. In another embodiment, B is aphenyl ring.

In another embodiment, D is —C(O)NR⁸⁰R⁸¹. In another embodiment, R⁸⁰ andR⁸¹ are each independently hydrogen, cycloalkyl or alkoxy. In anotherembodiment, R⁸⁰ is hydrogen. In another embodiment, R⁸¹ is cycloalkyl oralkoxy. In another embodiment, R⁸¹ is C₃₋₆cycloalkyl or C₁₋₆alkoxy. Inanother embodiment, R⁸¹ is cyclopropyl or methoxy.

In another embodiment, D is optionally substituted heteroaryl. Inanother embodiment, D is optionally substituted triazolyl. In anotherembodiment, D is 1,2,4-triazol-3-yl.

In another embodiment, R³ is hydrogen, optionally substitutedheterocyclyl, optionally substituted alkyl, C(L)R⁴⁰, halo, pseudohalo orOR⁴¹; where L is O, S or NR⁵⁵; R⁴⁰ is hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heteroarylium, optionally substituted cycloalkyl,optionally substituted heterocyclyl, C(L)R⁵⁶, halo pseudohalo, OR⁵⁵,SR⁵⁵, NR⁵⁷R⁵⁸ or SiR⁵²R⁵³R⁵⁴; R⁴¹ is hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heteroarylium, optionally substituted cycloalkyl,optionally substituted heterocyclyl, C(L)R⁵⁹, NR⁶⁰R⁶¹ or SiR⁵²R⁵³R⁵⁴;where R⁵², R⁵³ and R⁵⁴ are selected as in (i) or (ii) as follows (i)R⁵², R⁵³ and R⁵⁴ are each independently hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵or NR⁶²R⁶³; or (ii) any two of R⁵², R⁵³ and R⁵⁴ together form alkylene,alkenylene, alkynylene, heteroalkylene; and the other is selected as in(i); R⁵⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroarylium, cycloalkyl or heterocyclyl; R⁵⁶ is hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl,heterocyclyl, OR⁵⁵ or NR⁶⁴R⁶⁵; where R⁶⁴ and R⁶⁵ are each independentlyhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium,cycloalkyl, heterocyclyl, OR⁶⁶NR⁶²R⁶³, or R⁶⁴ and R⁶⁵ together formalkylene, alkenylene, alkynylene, heteroalkylene, where R⁶⁶ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl orheterocyclyl; R⁵⁷ and R⁵⁸ are selected as in (i) or (ii) as follows (i)R⁵⁷ and R⁵⁸ are each independently hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵, NR⁶⁷R⁶⁸or C(L)R⁶⁹, where R⁶⁷ and R⁶⁸ are each independently hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl orheterocyclyl, or together form alkylene, alkenylene, alkynylene,heteroalkylene; and R⁶⁹ is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁷⁰ or NR⁶²R⁶³,where R⁷⁰ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium,cycloalkyl, heterocyclyl; or (ii) R⁵⁷ and R⁵⁸ together form alkylene,alkenylene, alkynylene, heteroalkylene; R⁵⁹ is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR⁷⁰or NR⁶²R⁶³; R⁶⁰ and R⁶¹ are each independently hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl orC(L)R⁷¹, where R⁷¹ is alkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroarylium, cycloalkyl, heterocyclyl, OR⁵⁵ or NR⁶²R⁶³; or R⁶⁰ and R⁶¹together form alkylene, alkenylene, alkynylene, heteroalkylene; R⁶² andR⁶³ are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or R⁶² and R⁶³together form alkylene, alkenylene, alkynylene, heteroalkylene.

In another embodiment, R³ is hydrogen, optionally substitutedheterocyclyl, optionally substituted alkyl, C(L)R⁴⁰, halo or OR⁴¹. Inanother embodiment, R³ is hydrogen, optionally substituted heterocyclyl,optionally substituted alkyl, C(L)R⁴⁰, iodo, chloro or OR⁴¹. In anotherembodiment, R³ is hydrogen, optionally substituted dioxolanyl,optionally substituted methyl, C(L)R⁴⁰, iodo, chloro or OR⁴¹. In anotherembodiment, R³ is hydrogen, 2-dioxolanyl, optionally substituted methyl,C(O)R⁴⁰, iodo, chloro or OR⁴¹. In another embodiment, R³ is hydrogen,2-dioxolanyl, optionally substituted methyl, CHO, iodo, chloro or OR⁴¹.In another embodiment, R³ is hydrogen.

In another embodiment, R³ is optionally substituted methyl. In anotherembodiment, R³ is methyl which is optionally substituted withheterocyclyl, hydroxy, aralkylamino or heterocyclylalkylamino. Inanother embodiment, R³ is N-morpholinylmethyl, hydroxymethyl,N-(2-(3-chlorophenyl)-1-ethyl)aminomethyl,N-(2-morpholinyl-1-ethyl)aminomethyl or 4-piperizinylmethyl.

In another embodiment, A is O. In another embodiment, R⁴⁰ is hydrogen,optionally substituted alkyl or cycloalkyl. In another embodiment, R⁴⁰is hydrogen or alkyl. In another embodiment, R⁴⁰ is hydrogen.

In another embodiment, R⁴¹ is hydrogen or optionally substituted alkyl.In another embodiment, R⁴¹ is hydrogen, or alkyl optionally substitutedwith heterocyclyl, aryl, dialkylamino, halo or hydroxy. In anotherembodiment, R⁴¹ is hydrogen, or C₁₋₃alkyl optionally substituted withheterocyclyl, phenyl, dialkylamino, halo or hydroxy. In anotherembodiment, R⁴¹ is hydrogen, 2-(N-morpholinyl)eth-1-yl, benzyl,2-(N,N-di-(2-hydroxy-1-ethyl)amino)-1-ethyl, 2-bromo-1-ethyl,2,2-dioxolan-4-ylmethyl, 2-(4-methylpiperazin-1-yl)-1-ethyl or2,3-dihydroxy-1-propyl. In another embodiment, R⁴¹ is(S)-2,3-dihydroxy-1-propyl.

In another embodiment, R⁴ is hydrogen. In another embodiment, R⁵ isalkyl. In another embodiment R⁵ is methyl. In another embodiment, R⁶ ishydrogen.

In another embodiment, the compounds for use in the compositions andmethods provide herein have the above formulae, including formulae or apharmaceutically acceptable derivative thereof, where:

-   -   R¹ is hydrogen, acyl or —P(O)(OH)₂;    -   R² is hydrogen, halo, alkyl or alkylthio;    -   A is an aryl, heteroaryl or a heterocyclyl ring optionally fused        to a phenyl ring provided that the heterocyclyl ring is attached        to the carbonyl group via a carbon ring atom;    -   B is an aryl or heteroaryl ring;    -   D is heteroaryl, optionally substituted heteroaryl or        —C(O)NR⁸⁰R⁸¹ (where R⁸⁰ and R⁸¹ are independently hydrogen,        alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally        substituted heteroaryl);    -   R³ is selected from the group consisting of:        -   (a) amino, alkylamino or dialkylamino;        -   (b) acylamino;        -   (c) optionally substituted heterocyclyl;        -   (d) optionally substituted aryl or heteroaryl;        -   (e) heteroalkyl;        -   (f) heteroalkenyl;        -   (g) heteroalkynyl;        -   (h) heteroalkoxy;        -   (i) heteroalkylamino;        -   (j) optionally substituted heterocyclylalkyl;        -   (k) optionally substituted heterocyclylalkenyl;        -   (l) optionally substituted heterocyclylalkynyl;        -   (m) optionally substituted heterocyclylalkoxy or            heterocyclyloxy;        -   (n) optionally substituted heterocyclylalkylamino;        -   (o) optionally substituted heterocyclylalkylcarbonyl;        -   (p) heteroalkylcarbonyl;        -   (q) —NHSO₂R⁶ where R⁶ is alkyl, heteroalkyl or optionally            substituted heterocyclylalkyl;        -   (r) —NHSO₂NR⁷R⁸ where R⁷ and R⁸ are, independently of each            other, hydrogen, alkyl or heteroalkyl;        -   (s) —Y-(alkylene)-R⁹ where: Y is a single bond, —O—, —NH— or            —S(O)_(n) (where n is an integer from 0 to 2); and R⁹ is            cyano, optionally substituted heteroaryl, —COOH, —COR¹⁰,            —COOR¹¹, —CONR¹²R¹³, —SO₂R¹⁴, —SO₂NR¹⁵R¹⁶, —NHSO₂R¹⁷ or            —NHSO₂NR¹⁸R¹⁹, where R¹⁰ is alkyl or optionally substituted            heterocycle, R¹¹ is alkyl, and R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,            R¹⁸ and R¹⁹ are, independently of each other, hydrogen,            alkyl or heteroalkyl;        -   (t) —C(═NR²⁰)(NR²¹R²²) where R²⁰, R²¹ and R²² independently            represent hydrogen, alkyl or hydroxy, or R²⁰ and R²¹            together are —(CH₂)_(n)—where n is 2 or 3 and R²² is            hydrogen or alkyl;        -   (u) —NHC(X)NR²³R²⁴ where X is —O— or —S—, and R²³ and R²⁴            are, independently of each other, hydrogen, alkyl or            heteroalkyl;        -   (v) —CONR²⁵R²⁶ where R²⁵ and R²⁶ independently represent            hydrogen, alkyl, heteroalkyl or optionally substituted            heterocyclylalkyl, or R²⁵ and R²⁶ together with the nitrogen            to which they are attached form an optionally substituted            heterocyclyl ring;        -   (w) —S(O)_(n)R²⁷ where n is an integer from 0 to 2, and R²⁷            is alkyl, heteroalkyl, optionally substituted            heterocyclylalkyl or —NR²⁸R²⁹ where R²⁸ and R²⁹ are,            independently of each other, hydrogen, alkyl or heteroalkyl;        -   (x) cycloalkylalkyl, cycloalkylalkynyl and            cycloalkylalkynyl, all optionally substituted with alkyl,            halo, hydroxy or amino;        -   (y) arylaminoalkylene or heteroarylaminoalkylene;        -   (z) Z-alkylene-NR³⁰R³¹ or Z-alkylene-OR³² where Z is —NH—,            —N(lower alkyl)- or —O—, and R³⁰, R³¹ and R³² are            independently of each other, hydrogen, alkyl or heteroalkyl;        -   (aa) —OC(O)-alkylene-CO₂H or —OC(O)—NR′R″ (where R′ and R″            are independently hydrogen or alkyl); and        -   (bb) heteroarylalkenylene or heteroarylalkynylene;    -   R⁴ is selected from the group consisting of:        -   (a) hydrogen;        -   (b) halo;        -   (c) alkyl;        -   (d) alkoxy; and        -   (e) hydroxy;    -   R⁵ is selected from the group consisting of        -   (a) hydrogen;        -   (b) halo;        -   (c) alkyl;        -   (d) haloalkyl;        -   (e) thioalkyl;        -   (l) hydroxy;        -   (g) amino;        -   (h) alkylamino;        -   (i) dialkylamino;        -   (j) heteroalkyl;        -   (k) optionally substituted heterocycle;        -   (l) optionally substituted heterocyclylalkyl;        -   (m) optionally substituted heterocyclylalkoxy;        -   (n) alkylsulfonyl;        -   (o) aminosulfonyl, mono-alkylaminosulfonyl or            di-alkylaminosulfonyl;        -   (p) heteroalkoxy; and        -   (q) carboxy;    -   R⁶ is selected from the group consisting of:        -   (a) hydrogen;        -   (b) halo;        -   (c) alkyl; and        -   (d) alkoxy;    -   prodrugs, individual isomers, mixtures of isomers and    -   pharmaceutically acceptable salts thereof.

In another embodiment, the compounds are those wherein:

-   -   R¹ is hydrogen or acyl;    -   R² is hydrogen or alkyl;    -   A is an aryl or heteroaryl ring.

In another embodiment, the compounds are those wherein:

-   -   R¹ is hydrogen, acyl or —P(O)(OH)₂;    -   R² is hydrogen, halo, alkyl or alkylthio;    -   A is an aryl, heteroaryl or a heterocyclyl ring optionally fused        to a phenyl ring provided that the heterocyclyl ring is attached        to the carbonyl group via a carbon ring atom;    -   B is an aryl or heteroaryl ring;    -   R³ is selected from the group consisting of:        -   (a) amino;        -   (b) acylamino;        -   (c) optionally substituted heterocycle;        -   (d) heteroaryl optionally substituted with a substituent            selected from halo, alkyl or alkoxy;        -   (e) heteroalkyl;        -   (f) heteroalkenyl;        -   (g) heteroalkynyl;        -   (h) heteroalkoxy        -   (i) heteroalkylamino;        -   (j) optionally substituted heterocyclylalkyl;        -   (k) optionally substituted heterocyclylalkenyl;        -   (l) optionally substituted heterocyclylalkynyl;        -   (m) optionally substituted heterocyclylalkoxy;        -   (n) optionally substituted heterocyclylalkylamino;        -   (o) optionally substituted heterocyclylalkylcarbonyl;        -   (p) heteroalkylcarbonyl;        -   (q) —NHSO₂R⁶ where R⁶ is alkyl, heteroalkyl or optionally            substituted heterocyclylalkyl;        -   (r) —NHSO₂NR⁷R⁸ where R⁷ and R⁸ are, independently of each            other, hydrogen, alkyl or heteroalkyl;        -   (s) —Y-(alkylene)-R⁹ where: Y is a single bond, —O—, —NH— or            —S(O)_(n)— (where n is an integer from 0 to 2); and R⁹ is            cyano, heteroaryl, —COOH, —COR¹⁰, —COOR¹¹—CONR¹²R¹³, SO₂R¹⁴,            —SO₂NR¹⁵R¹⁶, NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹⁰ is alkyl or            optionally substituted heterocycle, R¹¹ is alkyl, and R¹²,            R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are, independently of            each other, hydrogen, alkyl or heteroalkyl;        -   (t) —C(═NR²⁰)(NR²¹R²²) where R²⁰, R²¹ and R²² independently            represent hydrogen, alkyl or hydroxy, or R²⁰ and R²¹            together are —(CH₂)_(n)— where n is 2 or 3 and R²² is            hydrogen or alkyl;        -   (u) —NHC(X)NR²³R²⁴ where X is -0- or —S—, and R²³ and R²⁴            are, independently of each other, hydrogen, alkyl or            heteroalkyl;        -   (v) —CONR²⁵R²⁶, where R²⁵ and R²⁵ independently represent            hydrogen, alkyl, heteroalkyl or optionally substituted            heterocyclylalkyl, or R²⁵ and R²⁶ together with the nitrogen            to which they are attached form an optionally substituted            heterocyclyl ring;        -   (w) —S(O)_(n)R²⁷ where n is an integer from 0 to 2, and R²⁷            is alkyl, heteroalkyl, optionally substituted            heterocyclylalkyl or —NR²⁸R²⁹ where R²⁸ and R²⁹ are,            independently of each other, hydrogen, alkyl or heteroalkyl;        -   R⁴ is selected from the group consisting of:            -   (a) hydrogen;            -   (b) halo;            -   (c) alkyl; and            -   (d) alkoxy;        -   R⁵ is selected from the group consisting of:            -   (a) hydrogen;            -   (b) halo;            -   (c) alkyl;            -   (d) haloalkyl;            -   (e) thioalkyl;            -   (f) hydroxy;            -   (g) amino;            -   (h) alkylamino;            -   (i) dialkylamino;            -   (j) heteroalkyl;            -   (k) optionally substituted heterocycle;            -   (l) optionally substituted heterocyclylalkyl; and            -   (m) optionally substituted heterocyclylalkoxy;        -   R⁶ is selected from a group consisting of:            -   (a) hydrogen;            -   (b) halo;            -   (c) alkyl; and            -   (d) alkoxy.

In another embodiment the compounds are those where R³ is:

-   -   (a) optionally substituted heterocyclyl;    -   (b) aryl or heteroaryl both optionally substituted with a        substituent selected from halo, alkyl, amino, alkoxy, carboxy,        lower alkoxy carbonyl, SO₂R′ (where R′ is alkyl) or —O₂NHR′R″        (where R′ and R″ are independently hydrogen or alkyl);    -   (c) heteroalkyl;    -   (d) heteroalkenyl;    -   (e) heteroalkylamino;    -   (f) heteraloxy    -   (g) optionally substituted heterocyclylalkyl or heterocyclyloxy;    -   (h) optionally substituted heterocyclylalkenyl;    -   (i) optionally substituted heterocyclylalkynyl;    -   (j) optionally substituted heterocyclylalkoxy;    -   (k) optionally substituted heterocyclylalkylamino;    -   (l) optionally substituted heterocyclylalkylcarbonyl:    -   (s) —Y-(alkylene)-R⁹ where Y is a single bond, —O or —NH— and R⁹        is optionally substituted heteroaryl, —CONR¹²R¹³, SO₂R¹⁴,        —SO₂NR¹⁵R¹⁶—NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵,        R¹⁶ R¹⁷, R¹⁸ and R¹⁹ are independently of each other        heteroalkyl; hydrogen, alkyl or heteroalkyl;    -   (t) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl,        all optionally substituted with alkyl, halo, hydroxy or amino;    -   (u) arylaminoalkylene or heteroarylaminoalkylene; or    -   (v) Z-alkylene-NR³⁰R³¹ where Z is —NH—, —N(alkyl)- or -0-, and        R³⁰ and R³¹ are independently of each other, hydrogen, alkyl or        heteroalkyl.

In still another embodiment, the compounds are those where R¹ and R² arehydrogen and B is phenyl. In an additional embodiment, the compounds arethose wherein R⁴ is hydrogen and R⁵ is halo or alkyl. In anotherembodiment, the compounds are those wherein R⁵ is chloro, fluoro ormethyl and R⁶ is hydrogen, chloro, fluoro, methyl or methoxy. In anotherembodiment, the compounds are those wherein R³ is optionally substitutedheteroaryl.

In yet another embodiment, the compounds are those wherein R³ ispyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxidopyridin-2-yl,N-oxidopyridin-3-yl, Noxidopyridin-4-yl or pyridon-2-yl, all optionallysubstituted. In a further embodiment, the compounds are those wherein R³is at the 3-position. In still another embodiment, the compounds arethose wherein R⁵ is 4-F or 2-Me, and R⁶ is hydrogen. In anotherembodiment, the compounds are those wherein R³ is optionally substitutedphenyl.

In a further embodiment, the compounds are those wherein R³ is3-sulfamoylphenyl, 3-methylsulfonylphenyl, 3-carboxyphenyl or3-ethoxycarbonylphenyl. In yet another embodiment, the compounds arethose wherein R⁵ is 4-F and R⁶ is hydrogen.

In another embodiment, the compounds are those wherein R³ is:

-   -   (a) heteroalkyl;    -   (b) heteroalkoxy;    -   (c) heteroalkylamino;    -   (d) optionally substituted heterocyclylalkyl;    -   (e) optionally substituted heterocyclylalkoxy;    -   (f) optionally substituted heterocyclylalkylamino;    -   (g) Y-(alkylene)-R⁹ where Y is a single bond, —O— or —NH— and R⁹        is optionally substituted heteroaryl, —CONR¹²R¹³, —SO₂R₁₄,        —SO₂NR¹⁵R₁₆, —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹ where R₁₂, R¹³, R¹⁴,        R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are independently of each other        hydrogen, alkyl or heteroalkyl; or    -   (h) Z-alkylene-NR³⁰R³¹ where Z is —NH—, —N(alkyl)- or —O—, and        R³⁰ and R³¹ are independently of each other, hydrogen, alkyl or        heteroalkyl.

In a further embodiment, the compounds are those wherein R³ isheteroalkyl. In another embodiment, the compounds are those wherein R³is at the 3-position and is selected from the group consisting of2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl,2-dimethylaminoethylamino, 3-dimethylaminopropylamino, hydroxymethyl,1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1-butyl or 3-hydroxybutyl. In yetanother embodiment, the compounds are those wherein R⁵ is 2-F and R⁶ is4-F.

In still another embodiment, the compounds are those wherein R⁵ is 2-Meand R⁶ is hydrogen. In an additional embodiment, the compounds are thosewherein R⁹ is heteroalkoxy or heteroalkylamino. In yet anotherembodiment, the compounds are those wherein R³ is at the 3-position andis selected from the group consisting of 3-dimethylaminopropoxy,2-dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy,2-dimethylaminoethylamino and 3-dimethylaminopropylamino.

In yet another embodiment, the compounds are those wherein R³ isoptionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkoxy or optionally substituted heterocyclylalkylamino. Instill another embodiment, the compounds are those wherein R³ is at the3-position and is selected from the group consisting of3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy,2-(2-oxo-pyrrolidin-1-yl)ethoxy, 3(morpholin-4-yl)propyl,2-(morpholin-4-yl)ethyl, 4-(morpholin-4-yl)butyl,3-(morpholin-4-yl)propylamino, 2-(morpholin-4-yl)ethylamino,4-hydroxypiperidinylmethyl, 2-(S,S-dioxothiamorpholin-4-yl)ethyl,3-(S,S-dioxo-thiamorpholin-4-yl)propyl and N-methylpiperazinylmethyl.

In an additional embodiment, the compounds are those wherein R³ is—Y-(alkylene)-R⁹ where Y is a single bond, —O— or —NH— and R⁹ isoptionally substituted heteroaryl, —CONR¹²R¹³, —SO₂R¹⁴,—SO₂NR¹⁵R¹⁶NHSO₂R¹⁷ or —NHSO₂NR′⁸R¹⁹ where R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁸ and R¹⁹ are independently of each other hydrogen, alkyl orheteroalkyl. In a further embodiment, the compounds are those wherein Yis a single bond and R⁹ is —SO₂R¹⁴ or —SO₂NR¹⁵R¹⁶.

In an additional embodiment, the compounds are those wherein R³ is5-methylsulfonylethyl or sulfamoylethyl.

Also provided herein is a compound selected from the group consisting of5-amino-1-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole,5-amino-1-(2,4-difluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole,5-amino-4-(3-aminobenzoyl)-1-(4-fluorophenyl)pyrazole,5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole,5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole,5-amino-4-(3-acetylaminobenzoyl)-1-phenylpyrazole,5-amino-4-[3-(2-aminoethyl)benzoyl]-1-(4-fluorophenyl)pyrazole,5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropylamino)benzoyl]pyrazole,5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazoleand 5-amino-1-(4-fluorophenyl)-4-(3-pyridin-3-ylbenzoyl)pyrazole.

Also provided herein is a compound selected from the group consisting of5-amino-1-(2-methylphenyl)-4-[3-pyridin-3-yl)benzoyl]pyrazole,5-amino-1-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole,5-amino-4-[3-(2,3-dihydroxypropoxy)benzoyl]-1-(4-fluorophenyl)pyrazole,5-amino-4-[3-(1,2-dihydroxyethyl)benzoyl]-1-(4-fluorophenyl)pyrazole,5-amino-1-(4-fluorophenyl)-4-[3-(sulfamoylbenzoyl]pyrazole,5-amino-1-(4-fluorophenyl)-4-[3-(3-hydroxy-3-methylbutyl)benzoyl]pyrazole,5-amino-1-(4-fluorophenyl)-4-[3-(2-(1-hydroxycyclopentyl)ethyl)benzoyl]pyrazole,5-amino-4-[3-(2-methylsulfonylethyl)benzoyl]-1-(4-fluorophenyl)pyrazole,and5-amino-1-(2,4-difluorophenyl)-4-[3-(2-hydroxyethylsulfonyl)benzoyl]pyrazole.

Further provided herein is a compound selected from3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide;3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-methoxy-4-methyl-benzamide;3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid;3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid;3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;{5-amino-1-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-1H-pyrazol-4-yl}-phenyl-methanone;3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-{5-amino-4-[3-(4-methyl-piperazin-1-ylmethyl)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;and3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide.

Also provided herein is a compound selected from3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide;3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-methoxy-4-methyl-benzamide;3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-{5-amino-1-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-1H-pyrazol-4-yl}-phenyl-methanone;3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-{5-amino-4-[3-(4-methyl-piperazin-1-ylmethyl)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;or 3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide.

Also provided is a compound selected from:

-   3-{5-Amino-4-[3-(2-dimethylamino-ethylcarbamoyl)-benzoyl]-imidazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(5-chloro-thiophene-2-carbonyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-hydrazinocarbonyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-cyclohexanecarbonyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-cyclopentanecarbonyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-phenylacetyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-ethylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;    and-   3-[5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide.

Also provided is a compound selected from:

-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methyl-1H-pyrazole-4-carboxylic    acid ethyl ester;-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic    acid ethyl ester;-   3-(5-Amino-4-cyclopentanecarbonyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-hydrazinocarbonyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic    acid benzylamide;-   3-(5-Amino-4-cyclohexanecarbonyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;    and-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic    acid cyclohexylamide.

Also provided is a compound selected from:

-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic    acid amide;-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methanesulfonyl-1H-pyrazole-4-carboxylic    acid amide;-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic    acid ethyl ester;-   5-Amino-3-[(3-chloro-benzylcarbamoyl)-methoxy]-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic    acid ethyl ester;-   3-[5-Amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-(2-hydroxy-ethoxy)-1H-pyrazole-4-carboxylic    acid ethyl ester;-   4-[5-Amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylic    acid tert-butyl ester;-   3-(5-Amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;    and-   3-[5-Amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide.

Also provided is a compound selected from:

-   3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide;-   3-(5-Amino-4-benzoyl-pyrazol-1-yl)-N-methoxy-4-methyl-benzamide;-   3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid;-   3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid;-   3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   {5-amino-1-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-1H-pyrazol-4-yl}-phenyl-methanone;-   3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-{5-amino-4-[3-(4-methyl-piperazin-1-ylmethyl)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-{5-Amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-cyclohexanecarbonyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-cyclopentanecarbonyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-Amino-4-phenylacetyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-{5-Amino-4-[3-(2-dimethylamino-ethylcarbamoyl)-benzoyl]-imidazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-ethylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-methylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-cyclopropylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(3-cyclopentylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-{5-Amino-4-[3-(morpholine-4-carbonyl)-benzoyl]-imidazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;-   3-{5-Amino-4-[3-(cyclopropylmethyl-carbamoyl)-benzoyl]-imidazol-1-yl}-N-cyclopropyl-4-methyl-benzamide;-   3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-(5-amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-amino-4-benzoyl-3-ethoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   3-[5-amino-4-benzoyl-3-(2-benzyloxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;-   4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylic    acid tert-butyl ester;-   3-[5-amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide,    trifluoroacetate salt;-   3-(5-amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   3-(5-amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide;-   5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic    acid amide;-   5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methanesulfonyl-1H-pyrazole-4-carboxylic    acid amide; and-   5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic    acid ethyl ester.

C. Preparation of the Compounds

Also provided herein is a process for preparing a compound of formula(I), which process involves the steps of:

-   -   (i) reacting a 2-keto-3-phenylaminoacrylonitrile of formula 1:

with a hydrazine of formula 2:

where R³, R⁴, R⁵ and R⁶ are as defined herein to provide a compound offormula (I)where R¹ is hydrogen; or

-   -   (ii) reacting a 2-keto-3-phenylaminoacrylonitrile of formula 3:

where Z is either hydroxy, nitro or halo group and R^(b) is as definedherein with a hydrazine of formula 2 to provide a compound of formula 4:

followed by conversion of the Z group to the desired R³ group to providea compound of formula (I) where R¹ is hydrogen;

-   -   (iii) optionally modifying any of the R¹, R³, R⁵ or R⁶ groups;    -   (iv) optionally converting the compound of formula (I) prepared        in steps (i), (ii) or (iii) above to the corresponding acid        addition salt by treatment with an acid;    -   (v) optionally converting the compound of formula (I) prepared        in steps (i), (ii) or (iii) above, to the corresponding free        base by treatment with a base; and    -   (vi) optionally separating a mixture of stereoisomers of a        compound of formula (I) prepared in steps (i)-(v) above, to give        a single stereoisomer.

Also provided herein is a process for preparing a compound of formula(I), which process involves reacting a compound of formula 5:

where R⁵ and R⁶ are as defined herein and L is a leaving group underorganometallic displacement reaction conditions, including, but notlimited to, halo, pseudohalo, aryloxy, perfluoroaryloxy, N-alkoxyamino,including N-methoxyamino, with an organometallic reagent of formula:

where R³ and R⁴ are as defined herein and M is a metallic moiety,including, but not limited to, an alkali metal, an alkaline earth metal,and a transitional metal, such as Li, K and Mg, to provide a compound offormula (I) where R¹ is hydrogen;

-   -   (ii) optionally modifying any of the R′, R³, R⁴, R⁵ or R⁶        groups;    -   (iii) optionally converting the compound of formula (I) prepared        in steps (i) or (ii) above, to the corresponding acid addition        salt by treatment with an acid;    -   (iv) optionally converting the compound of formula (I) prepared        in steps (i) or (ii) above, to the corresponding free base by        treatment with a base; and optionally separating a mixture of        stereoisomers of a compound of formula (I) prepared in steps (i)        or (iv) above, to give a single stereoisomer.

The compounds disclosed herein are merely exemplary, and one skilled inthe art can be readily prepare compounds in the same manner as thatdisclosed herein using well known methods of chemical synthesis,including methods similar to those exemplified herein.

Compounds provided herein may generally be prepared according to thefollowing schemes and the knowledge of one skilled in the art.Additional synthetic methods are described, for example, in U.S. Pat.Nos. 6,376,527; 6,316,466 and 6,444,696, and International PatentApplication Publication No. WO 99/57101, each of which is incorporatedherein by reference.

In addition to the documents incorporated by reference we disclose thefollowing non-limiting examples of methods useful for the production ofcompounds provided herein (see, Schemes 1-8, infra).

Amines attached to aryl or heteroaryl ring systems are useful asintermediates in the preparation of the compounds provided herein. Thereare many methods of preparing such intermediates known to one skilled inthe art of organic chemistry. Several methods of preparing amines usefulin the preparation of the compounds provided herein are illustrated inschemes 1-7.

Substituted aniline of type (II) useful herein can be prepared fromcommercially available 3-amino-4-methylbenzoic acid as depicted inScheme 1, using methods similar to those disclosed in InternationalPatent Application Publication No. WO 02/40486. Aniline is protected bya Boc group. This is followed by condensation with methylamine using thecoupling agent EDC and HOBt. The Boc group is then removed by HCl indioxane to give the desired substituted aniline of type (II) as ahydrochloride salt.

Substituted anilines of type (III) useful herein can be prepared fromcommercially available 3-amino-4-methylbenzoic acid as depicted inScheme 2. Condensation with cyclopropylamine using the coupling agentEDC affords an aniline of type (III).

Substituted anilines of type (IV) useful herein can be prepared fromcommercially available 4-methyl-3-nitrobenzoic acid as depicted inScheme 3, using methods similar to those disclosed in InternationalPatent Application Publication No. WO 03/033482. Condensation of theacid with t-butoxy-carbonylhydrazide using the coupling agent HBTU andHOBt affords the protected acyl hydrazide. Deprotection with TFA,followed by condensation with triethyl orthoformate yields theoxadiazolyl-substituted nitrotoluene. Hydrogenation of the nitro groupgives the desired aniline of type (IV).

Substituted anilines of type (V) useful herein can be prepared fromcommercially available 4-methyl-3-nitrobenzamide as depicted in Scheme4, using methods described by Han et al. [J. Med. Chem., 41, 2019-2028(1998)]. The indicated aryl carboxamide was condensed withN,N-dimethylformamide diethyl acetal. This was followed by reaction withhydrazine in acetic acid to form a triazolyl-substituted nitrotoluene.Hydrogenation of the nitro group gives the desired aniline of type (V).

Substituted anilines of type (VI) useful herein can be prepared fromcommercially available methyl 4-iodobenzoate as depicted in Scheme 5.Nitration of an aromatic precursor followed by reduction of the nitrogroup yields the aniline. Palladium-catalyzed coupling withethynyltrimethylsilane, followed by desilylation and saponificationgives the desired ethynyl-substituted aminobenzoic acid. Coupling withmethoxyamine using the coupling agent EDC affords the desired aniline(VI). See, e.g., Eur. J. Org. Chem., 4607 (2001).

Alternatively, a substituted aniline of type (VI) useful herein can beprepared from 4-amino-3-nitrobenzoic acid as depicted in Scheme 6.Iodide substitution of the aryldiazonium salt, followed byesterification with methanol gives methyl 4-iodo-3-nitrobenzoate. Thenitro group can be reduced by SnCl₂ to give the desired aniline.Palladium catalyzed coupling with ethynyltrimethyl-silane, followed bydesilylation and saponification yields the ethynyl-substitutedaminobenzoic acid. Coupling with methoxyamine using the coupling agentEDC affords the aniline (VI). See, e.g., Eur. J. Org. Chem., 4607(2001).

As depicted in Scheme 7, substituted anilines of type (VII) usefulherein can be prepared from intermediate methyl 4-iodo-3-nitrobenzoate,which can be synthesized as shown in Scheme 6. Palladium catalyzedcoupling with vinyltributyltin followed by carbene addition to theresulting styrene double bond gives the cyclopropyl substituted methylnitrobenzoate. Reduction of the nitro group followed by Boc protectionand saponification gives the protected 3-amino-4-cyclopropylbenzoicacid. Coupling with an alkoxyamine using the coupling agent EDC affordsthe desired aniline (VII). See, e.g., International Patent ApplicationPublication Nos. WO 02/092087 and WO 02/40486.

Hydrazines attached to aryl or heteroaryl ring systems are useful asintermediates herein. There are many methods of preparing suchintermediates known to one skilled in the art of organic chemistry. Onemethod of preparing some of the hydrazines useful herein is illustratedin Scheme 8.

Aryl hydrazines of type (VIII) useful herein can be prepared from3-amino-N-methoxy-4-methylbenzamide hydrochloride, which itself can beprepared according the methods disclosed in International PatentApplication Publication No. WO 02/40486. Through the formation of thearyldiazonium salt and its subsequent reduction by SnCl₂, the desiredhydrazine of type (VIII) is obtained.

Also as depicted in Scheme 8, aryl hydrazines of type (IX) useful hereincan be prepared from 3-amino-N-cyclopropyl-4-methylbenzamide, whichitself can be prepared according to the methods depicted in Scheme 2.Through the formation of the aryldiazonium salt and its subsequentreduction by SnCl₂, the desired hydrazine of type (IX) is obtained.

Similarly, other hydrazines can also be prepared from amines such asthose described above in Schemes 1-7.

Also, as depicted in Scheme 9, acrylonitriles of type (X) useful hereincan be prepared from an aryl ester and acetonitrile. Acetonitrile can betreated with lithium diisopropylamide in THF at −78° C., followed by theaddition of the aryl ester to give the correspondingaryloylacetonitrile. This intermediate is then reacted withN,N′-diphenylformamidine in a solvent such as toluene at relfux to givethe desired corresponding acrylonitrile of type (X).

Also, as depicted in Scheme 10, aminopyrazoles of type (XI) usefulherein can be prepared from an acrylonitrile of type (X), which itselfcan be prepared according to the methods depicted in Scheme 9, andhydrazines such as those of type (VIII) and (IX), which themselves canbe prepared according to the methods depicted in Scheme 8. Theacrylonitrile and the hydrazine are heated to 60 to 100° C. in a solventsuch as DMF or ethanol to give the desired aminopyrazole of type (XI).

Also, as depicted in Scheme 11, aminopyrazoles of type (XIII) usefulherein can be prepared from an acrylonitrile of type (XII), which itselfcan be prepared by treatment of an acrylonitrile of type (X), preparedaccording to the methods depicted in Scheme 9, with sodium hydride andcarbon disulfide followed by treatment with iodomethane, and hydrazinessuch as those of type (VIII) and (IX), which themselves can be preparedaccording to the methods depicted in Scheme 8. The acrylonitrile and thehydrazine are heated to 60 to 100° C. in a solvent such as DMF orethanol to give the desired aminopyrazole of type (XIII).

Also, as depicted in Scheme 12, aminopyrazoles of type (XIV) usefulherein can be prepared from an acrylonitrile of type (XII), which itselfcan be prepared according to the methods depicted in Scheme 11, andhydrazines such as those of type (VIII) and (IX), which themselves canbe prepared according to the methods depicted in Scheme 8. Treatment ofthis intermediate (XII) with an alcohol alkoxide prior to with heatingat 60 to 100° C. with the hydrazine in a solvent such as DMF or ethanolgives the desired aminopyrazole of type (XIII).

Also, as depicted in Scheme 13, aminoimidazoles of type (XV) usefulherein can be prepared from substituted anilines of type (III), whichthemselves can be prepared according to the methods depicted in Scheme2. The aniline is heated in triethyl orthoformate. After removal of thesolvent in vacuo, the product was reacted with aminomalononitrilep-toluenesulfonate and sodium acetate in acetic acid to give theaminocyanoimidazole intermediate. Reaction of this intermediate with aGrignard reagent gives the desired aminoimidazole of type (XV).

Compounds provided herein can be prepared from hydrazines attached toaryl or heteroaryl ring systems using methods disclosed in U.S. Pat.Nos. 6,316,466, 6,376,527 and 6,444,696.

Additional synthetic methods useful in the synthesis of the compoundsprovided herein are disclosed in the following, the disclosures of whichare incorporated herein by reference in their entirety:

-   -   1) J. Heterocyclic Chem. 17, 631 (1980)    -   2) Tetrahedron 55(48), 13703 (1999)    -   3) European Patent No. EP 0 713 876    -   4) Chemische Berichte 126(10), 2317 (1993)    -   5) Journal of Organic Chem. 58(24), 6620 (1993)    -   6) Tetrahedron Letters 35, 3239 (1973)    -   7) Journal of Chemical Research, Synopses 1, 2 (1997)    -   8) Boletin de la Sociedad Quimica del Peru 53(3), 150 (1987)    -   9) Journal of the Chemical Society, Chemical Communications 2,        35 (1973)    -   10) Comptes Rendus des Seances de l'Academie des Sciences,        Series C: Sciences Chimiques 274(20), 1703 (1972)

Also provided herein are compounds prepared according to a processdisclosed herein.

D. Formulation of Pharmaceutical Compositions

Also provided herein is a pharmaceutical composition comprising acompound provided herein. The composition can be used, for example, as amedicament. The composition can contain, for example, a pharmaceuticallyacceptable excipient or carrier. A composition or medicament providedherein can be used for the treatment, prevention or amelioration of oneor more symptoms of p38 kinase mediated diseases or disorders, includinginflammatory diseases.

Thus, provided herein are pharmaceutical compositions capable oftreating p38-kinase-associated conditions, including TNF-α, IL-1, and/orIL-8 mediated conditions, as described above. The compositions maycontain other therapeutic agents, as described herein, and may beformulated, for example, by employing conventional solid or liquidvehicles or diluents, as well as pharmaceutical additives of a typeappropriate to the mode of desired administration (e.g., excipients,binders, preservatives, stabilizers, flavors, etc.) according totechniques such as those well known in the art of pharmaceuticalformulation.

The compounds provided herein may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally useful for skin-related diseases, andsystemic treatment is generally used for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps. Exemplarycompositions for topical administration include a topical carrier suchas PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered by,sublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agentsand stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The effective amount of a compound provided herein may be determined byone of ordinary skill in the art, and includes exemplary dosage amountsfor a mammal of from about 0.05 to 100 mg/kg of body weight of activecompound per day, which may be administered in a single dose or in theform of individual divided doses, such as from 1 to 4 times per day. Itwill be understood that the specific dose level and frequency of dosagefor any particular subject may be varied and will depend upon a varietyof factors, including the activity of the specific compound employed,the metabolic stability and length of action of that compound, thespecies, age, body weight, general health, sex and diet of the subject,the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition. Subjects fortreatment include animals, generally mammalian species such as humans,and domestic animals such as dogs, cats, horses, and the like. Thus,when the term “patient” is used herein, this term is intended to includeall subjects, in particular mammalian species, including humans, thatare affected by mediation of p38 enzyme levels.

Also provided in one embodiment is a process for the manufacture ofmedicaments which process involves bringing a compound provided hereintogether with a pharmaceutically acceptable excipient and bringing themixture into a galenical administration form.

E. Methods of Use of the Compounds and Compositions

In a further embodiment, the compounds provided herein can be used inthe treatment, prevention, or amelioration of one or more symptoms ofinflammatory diseases. A compound provided herein can be used, inanother embodiment, for the manufacture of a medicament for thetreatment orprophylaxis of inflammatory diseases.

The compounds provided herein are selective inhibitors of p38 kinaseactivity, and in particular, isoforms p38α and p38β. Accordingly,compounds provided herein are useful for treating conditions associatedwith p38 kinase activity. Such conditions include diseases in whichcytokine levels are modulated as a consequence of intracellularsignaling via p38, and in particular, diseases that are associated withan overproduction of cytokines IL-1, IL-4, IL-8, and TNF-α. Providedherein are methods of treating a disease by administering a compoundprovided herein that inhibits p38 kinase activity. Also provided hereinare methods for inhibiting or delaying the onset of a disease ordisorder by administering a compound provided herein. Methods providedherein can be used to achieve a full or partial reduction of thesymptoms of a disease or disease state, and/or to alleviate, ameliorate,or lessen, the disease or disorder and/or its symptoms. When referenceis made herein to inhibition of “p-38α/βkinase,” this means that eitherp38α and/or p38β kinase are inhibited. Thus, reference to an IC₅₀ valuefor inhibiting p-38α/β kinase means that the compound has sucheffectiveness for inhibiting at least one of, or both of, p38α and p38βkinases.

In view of their activity as inhibitors of p38α/β kinase, compoundsprovided herein are useful in treating p-38 associated conditionsincluding, but not limited to, inflammatory diseases, autoimmunediseases, destructive bone disorders, proliferative disorders,angiogenic disorders, infectious diseases, neurodegenerative diseases,and viral diseases.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoisosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, meloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis and multiple myeloma-related bone disorder, acutemyelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma,Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, andShigellosis; Alzheimer's disease, Parkinson's disease, cerebralischemias or neurodegenerative disease caused by traumatic injury;angiogenic disorders including solid tumors, ocular neovasculization,and infantile haemangiomas; viral diseases including acute hepatitisinfection (including hepatitis A, hepatitis B and hepatitis C), HIVinfection and CMV retinitis, AIDS, SARS, ARC or malignancy, and herpes;stroke, myocardial ischemia, ischemia in stroke heart attacks, organhyposia, vascular hyperplasia, cardiac and renal reperfusion injury,thrombosis, cardiac hypertrophy, thrombin induced platelet aggregation,endotoxemia and/or toxic shock syndrome, and conditions associated withprostaglandin endoperoxidase synthase-2.

In addition, p38 inhibitors provided herein inhibit the expression ofinducible pro-inflammatory proteins such as prostaglandin endoperoxidesynthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2).Accordingly, additional p38-associated conditions include edema,analgesia, fever and pain, such as neuromuscular pain, headache, paincaused by cancer, dental pain and arthritis pain. The inventivecompounds also may be used to treat veterinary viral infections, such aslentivirus infections, including, but not limited to equine infectiousanemia virus; or retro virus infections, including felineimmunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus. When the terms “p38-associated condition” or“p38-associated disease or disorder” are used herein, each is intendedto encompass all of the conditions identified above as if repeated atlength, as well as any other condition that is affected by p38 kinaseactivity.

Thus, provided herein are methods for treating such conditions,involving administering to a subject in need thereof an effective amountof at least one compound provided herein or a pharmaceuticallyacceptable derivative thereof. The methods of treating p38kinase-associated conditions may involve administering compoundsprovided herein alone or in combination with each other and/or othersuitable therapeutic agents useful in treating such conditions.Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, CSAIDs, 4-substituted imidazo[1,2-A]quinoxalinesas disclosed in U.S. Pat. No. 4,200,750 and in S. Ceccarelli et al.(1998) European Journal of Medicinal Chemistry 33:943-955;interleukin-10, glucocorticoids, salicylates, nitric oxide, and otherimmunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf);cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-αinhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor,and rapamycin (sirolimus or Rapamune) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds provided herein, may be used, for example, in thoseamounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsprovided herein, such other therapeutic agent(s) may be administeredprior to, simultaneously with, or following the administration of theinventive compounds.

The following Examples illustrate embodiments herein, and are notintended to limit the scope of the claims. Abbreviations employed in theExamples are defined below. Compounds of the Examples are identified bythe example and step in which they are prepared (for example, “1A”denotes the title compound of step A of Example 1), or by the exampleonly where the compound is the title compound of the example (forexample, “2” denotes the title compound of Example 2).

ABBREVIATIONS

-   Ph=phenyl-   Bz=benzyl-   t-Bu=tertiary butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   Iso-P or i-Pr=isopropyl-   MeOH=methanol-   EtOH=ethanol-   EtOAc=ethyl acetate-   Boc=tert-butyloxycarbonyl-   CBZ=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   DCM or CH₂Cl₂=dichloromethane-   DCE=1,2-dichloroethane-   DMF=dimethyl formamide-   DMSO=dimethyl sulfoxide-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   HATU=O-(7-Azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronim    hexafluorophosphate-   KOH=potassium hydroxide-   K₂CO₃=potassium carbonate-   POCl₃=phosphorous oxychloride-   KOtBu=potassium t-butoxide-   EDC or EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   DIPEA=diisopropylethylamine-   HOBt=1-hydroxybenzotriazole hydrate-   m-CPBA=m-chloroperbenzoic acid-   NaH=sodium hydride-   NaOH=sodium hydroxide-   Na₂S₂O₃=sodium thiosulfate-   Na₂SO₄=sodium sulfate-   Pd=palladium-   Pd/C=palladium on carbon-   min=minute(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   RT or rt=room temperature-   ret. t. or t_(R)=HPLC retention time (minutes)-   sat or sat'd=saturated

General Methods.

Mass spectral data were obtained on a Thermo Finnigan LCQ Duo Ion Trapmass spectrometer. In the Examples: “HPLC (6 minute gradient)” refers toKeystone C18 Beta Basic column, 0.4 mL/min flow rate, 6 minute lineargradient elution (start solvent % B=0; final solvent % B=100), solventA: acetonitrile+0.025% TFA; solvent B=H₂O+0.025% TFA. “HPLC (4 minutegradient)” refers to Keystone C18 Beta Basic column, 0.5 mL/min flowrate, 4 minute linear gradient elution (start solvent % B=0; finalsolvent % B=100), solvent A: acetonitrile+0.025% TFA; solventB=H₂O+0.025% TFA.

Example 1 Preparation of3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide

A. 3-Hydrazino-N-methoxy-4-methyl-benzamide

To a stirred solution of 3-amino-N-methoxy-4-methyl-benzamide 1 (102 mg,0.56 mmol, preparation: International Patent Application Publication No.WO 02/40486 A2, pg. 66) in water (5 ml) at 0° C. was added conc. HCl (5mL) followed by the addition of sodium nitrite (43 mg, 0.62 mmol). Thereaction mixture was stirred at 0° C. for 40 min then a solution oftin(II)chloride (241 mg, 1.27 mmol) in conc. HCl (1 mL) was added andthe mixture was stirred for 1 hr then allowed to stand at −20° C. for 20hr before it was warmed to RT and concentrated to a white solid. Thesolid was triturated with ethanol, the solids were filtered, and thefiltrate concentrated to provide3-hydrazino-N-methoxy-4-methyl-benzamide 2 as white solid (486 mg) as amixture with tin salts and ethanol which was used without furtherpurification. HPLC (6 minute gradient) t_(R) 0.78 min; MS m/z 195.9[M+H]⁺.

B.3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide

To a stirred solution 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (116mg, estimated 0.14 mmol) in EtOH (10 ml) was added2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 3 (59 mg, 0.14 mmol,preparation: International Patent Application Publication No. WO02/57101 A1, pg. 84) and mixture was heated (bath T=65-70° C.) for 4 hr,when additional 3-hydrazino-N-methoxy-4-methyl-benzamide 2 (80 mg, 0.11mmol) was added and the mixture was heated at the same temperature for27 hr. It was cooled to room temperature, concentrated and redissolvedin EtOAc before it was washed with water and brine, dried over Na₂SO₄,concentrated to give a crude semisolid. The mixture was then purified byflash chromatography, eluting with 1:1 EtOAc/hexanes to removeimpurities then 100% EtOAc give3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-methoxy-4-methyl-benzamide4 as an off-white solid (38 mg, 0.08 mmol, 55%). HPLC (6 minutegradient) t_(R) 3.49 min; MS m/z 476.96 [M+H]⁺; ¹H NMR (CD₃OD, 300 MHz)δ 8.10 (s, 1H), 7.95 (d, J=8.0, 1H), 7.88 (d, J=8.0, 1H), 7.82 (m, 2H),7.78 (s, 1H), 7.58 (d, J=8.0, 1H), 7.33 (t, J=7.8, 1H), 5.02 (s. 3H),2.33 (s, 3H) ppm; ¹³C NMR (DMSO-d₆, 125 MHz) δ 189.3, 154.3, 143.5,143.3, 142.0, 138.3, 137.4, 133.5, 132.9, 132.0, 130.4, 128.8, 128.4,104.8, 95.4, 64.8, 18.2 ppm.

Example 2 Preparation of3-(5-Amino-4-benzoyl-pyrazol-1-yl)-N-methoxy-4-methyl-benzamide

To a stirred solution of 3-amino-N-methoxy-4-methyl-benzamide 1 (104 mg,0.58 mmol) in water (2 ml) at 0° C. was added conc. HCl (2 mL) followedby the addition of sodium nitrite (44 mg, 0.63 mmol). The reactionmixture was stirred at 0° C. for 40 minutes then a solution oftin(II)chloride (245 mg, 1.30 mmol) in conc. HCl (1 mL) was added andthe mixture was stirred for 40 minutes then allowed to stand at −20° C.for 20 hours before it was warmed to RT and concentrated to a whitesolid. The solid was triturated with ethanol, the solids were removed,and 2-benzoyl-3-phenylamino-acrylonitrile 5 (144 mg, 0.58 mmol,preparation: Grothaus, J. Am. Chem. Soc. 58, 1334 (1936)) was added andthe mixture heated (bath T=65-70° C.) for 16 hr. The mixture was cooledto RT, concentrated and purified by flash chromatography, eluting with1:1 EtOAc/hexanes to remove impurities then 100% EtOAc to give3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-methoxy-4-methyl-benzamide 6 as anoff-white solid (41 mg, 0.12 mmol, 28%). HPLC (4 minute gradient) t_(R)1.93 min; MS m/z 351.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 11.88 (s 1H,NH), 7.803 (m, 4H), 7.56 (m, 4H), 7.01 (s, 2H, NH₂), 3.32 (s, 3H), 2.162(s, 3H) ppm; ¹³C NMR (DMSO-d₆, 125 MHz) δ 187.6, 151.9, 141.2, 139.7,139.6, 135.7, 131.4, 131.2, 130.9, 128.5, 128.1, 127.8, 126.4, 102.6,63.2, 17.2 ppm.

Example 3 Preparation of3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid

A. 3-Hydrazino-4-methyl-benzoic acid hydrochloride

To a stirred solution of 3-amino-4-methylbenzoic acid 1 (5.64 g, 31.2mmol, 1.0 eq) in 100 mL of dioxane and 100 mL of water at 0° C. wasadded 100 mL of conc. HCl followed by the portionwise addition of sodiumnitrite (2.82 g, 40.9 mmol, 1.1 eq) as a solid at a rate to control gasevolution and foaming over 45 minutes. A clear brown solution resulted.Anhydrous tin(II)chloride (15.62 g, 83.7 mmol, 2.25 eq) was dissolved inconc. HCl (25 mL) and added dropwise over 25 mL at 0° C. After 1 hour,the precipitate was filtered and washed with dioxanes then dried undervacuum to provide 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 as atan solid (4.98 g, 66%): HPLC (4 minute gradient) t_(R) 0.97 min; MS m/z167 [M+1-1]⁺; ¹H (300 MHz, DMSO-d₆) δ 10.03 (s, 1H, COOH), 7.89 (s, 1H),7.51 (s, 1H), 7.27 (d, J=8.0, 1H), 3.38 (s, 3H, NHNH ₂), 2.23 (s, 3H)ppm.

B. 3-(5-Amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid

To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride2 (242 mg, 1.19 mmol, 1.0 eq) in 25 mL of ethanol was added2-benzoyl-3-phenylamino-acrylonitrile 4 (296 mg, 1.19 mmol, 1.0 eq,preparation: Grothasu, Davis, J. Am. Chem. Soc., 58, 1334 (1936)) andtriethylamine (161 μL, 1.19 mmol, 1.0 eq) and the mixture was heated to65° C. All solids dissolved when temperature reached 65° C. After threehours, LC-MS indicates consumption of the hydrazine. The solids werefiltered to provide 3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoicacid 5 (95 mg, 25%) as a beige solid: HPLC (4 minute gradient) t_(R)2.10 min; MS m/z 322 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 7.99 (d, J=7.6,1H), 7.81 (s, 2H), 7.78 (s, 1H), 7.57 (m, 4H), 7.02 (s, 2H, (s, 3H) ppm;¹³C NMR (DMSO-d₆, 75 MHz) δ 187.6, 166.3, 152.0, 141.3, 141.2, 139.6,135.9, 131.6, 131.2, 130.1, 129.8, 128.6, 127.8, 102.6, 17.4 ppm.

Example 4 Preparation of3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid 5 (Example 3,700 mg, 2.18 mmol, 1.0 eq) in 30 mL of DMF was added EDCI (855 mg 4.35mmol, 2.0 eq), HOBt (589 mg, 4.35 mmol, 2.0 eq), anddiisopropylethylamine (1.59 mL, 8.71 mmol, 4.0 eq) and the solution wasstirred for 15 minutes at room temperature when cyclopropylamine (302μL, 4.35 mmol, 2.0 eq) was added and the reaction stirred for 1 hour.The mixture was diluted with EtOAc (300 mL) and washed with water (2×25mL) and brine (25 mL), dried (Na₂SO₄) and concentrated. The product waspurified by flash chromatography on silica gel eluted with 8/2EtOAc/MeOH to provide the product as a brown oil. The product wasfurther purified by trituration with 1/1/1 EtOAc/hexanes/CH₂Cl₂ anddried under vacuum to provide3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 6(387 mg, 50%) as a white powder: HPLC (4 minute gradient) t_(R) 2.11min; MS m/z 361 [M+H]; ¹H NMR (CD₃OD, 300 MHz) δ 7.92 (d, J=7.6, 1H),7.81 (m, 4H), 7.54 (m, 4H), 2.85 (m, 1H), 2.22 (s, 3H), 0.80 (d, J=5.7,2 H), 0.63 (s, 2H) ppm; ¹³C NMR (CD₃OD, 75 MHz) δ 191.2, 170.1, 153.8,143.3, 142.0, 141.1, 136.9, 134.8, 132.9, 132.7, 130.1, 129.7, 129.2,128.1, 104.8, 24.1, 17.7, 6.6 ppm.

Example 5 Preparation of3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid

To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride1 (Example 3A, 314 mg, 1.54 mmol, 1.0 eq) in 50 mL of ethanol and 5 mLof methanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2(579 mg, 1.54 mmol, preparation: International Patent ApplicationPublication No. WO 02/57101 A1, pg. 84). The mixture was heated to 75°C. for 18 h. The precipitated solids were collected on a fritted filterand were washed with ethanol to provide3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid 3 (153mg, 22%) as a white solid. MS m/z 448 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆)δ2.18 (s, 3H), 7.05 (bs, 2H), 7.34 (dd, J₁=J₂=7.7 Hz), 7.58 (d, J=8.1Hz, 1H), 7.78 (s, 1H), 7.81 (m, 2H), 7.94 (m, 1H), 7.98 (m, 1H), 8.03(m, 1H) ppm.

Example 6 Preparation of3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 3-(N′-tert-Butoxycarbonyl-hydrazino)-4-methyl-benzoic acid

3-Hydrazino-4-methyl-benzoic acid hydrochloride 1 (Example 3A, 13 g,64.5 mmol) was dissolved into dioxane (200 mL) and H₂O (100 mL). AqueousNaOH (5.16 g NaOH in 100 mL H₂O, 2×64.5 mmol) was added followed by theaddition of (Boc)₂O (15.5 g, 1.1×64.5 mmol) immediately. The reactionmixture was stirred at room temperature for 2 hrs. Concentrated onrotavapor. Then H₂O and CH₂Cl₂ (some MeOH) were added. With stirringstrong H⁺ resin was added to neutralize the mixture to pH<2. Filteredand the resin was washed with CH₂Cl₂ and MeOH. The aqueous layer waswashed with CH₂Cl₂ (added some MeOH) for two times. The combined organiclayer was dried over Na₂SO₄ (some EtOAc was added). Filtration andconcentration gave 3-(N′-tert-butoxycarbonyl-hydrazino)-4-methyl-benzoicacid 4 (16 g, 94%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ1.48 (s,9H), 2.27 (s, 3H), 5.76 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.7Hz, 1H), 7.61 (s, 1H) ppm.

B. N′-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-hydrazinecarboxylic acidtert-butyl ester

3-(N′-tert-Butoxycarbonyl-hydrazino)-4-methyl-benzoic acid 4 (14 g, 52.6mmol) was dissolved in DMF (250 mL). EDCI (20 g, 105.2 mmol) and HOBt(16 g, 105.2 mmol) were added. The mixture was stirred at roomtemperature for 30 min. Cyclopropylamine (7.4 mL, 105.2 mmol) was added,followed by DIPEA (37 mL, 4×52.6 mmol). The reaction mixture was stirredat room temperature for 18 h. After concentration of the reactionmixture in vacuo, H₂O was added. The mixture was then extracted withCH₂Cl₂ three times. The organic layer was washed with aqueous NaClsolution. Dried over Na₂SO₄, filtration and concentration gave a whitesolid. The crude product was dissolved in CH₂Cl₂/MeOH, and then purifiedby silica gel column chromatography (CH₂Cl₂/EtOAc, gradient 2/1 to 1/1)to give the desire product. The product was further purified byrecrystallization from EtOAc/CH₂Cl₂; washing of the collected solidswith EtOAc gaveN′-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-hydrazinecarboxylic acidtert-butyl ester 5 (11 g, 69%). ¹H NMR (300 MHz, CDCl₃) δ0.58 (m, 2H),0.84 (m, 2H), 1.48 (s, 9H), 2.23 (s, 3H), 2.87 (m, 1H), 5.69 (bs, 1H),6.17 (bs, 1H), 6.39 (brs, 1H), 7.70 (m, 2H), 7.32 (s, 1H) ppm.

C. N-Cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroacetic acidsalt

N′-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-hydrazinecarboxylic acidtert-butyl ester 5 was dissolved in CH₂Cl₂/TFA (2/1) with 2% H₂O and themixture was stirred at room temperature for 3 hrs. Concentration invacuo gave a syrup. CH₂Cl₂ and toluene was added, and concentration invacuo again gave N-cyclopropyl-3-hydrazino-4-methyl-benzamide,trifluoroacetic acid salt 6 as an off-white solid. (Yield: 100%). MS m/z206 [M+H]⁺; ¹H NMR (300 MHz, D₂O) δ0.68 (m, 2H), 0.88 (m, 2H), 2.31 (s,3H), 2.79 (m, 1H), 7.31 (s, 1H), 7.36 (bs, 2H) ppm.

D.3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of N-cyclopropyl-3-hydrazino-4-methyl-benzamide,trifluoroacetic acid salt 6 (648 mg, 1.74 mmol, 1.0 eq) in 2 mL ofethanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (550mg, 1.74 mmol, preparation: International Patent Application PublicationNo. WO 02/57101 A1, pg. 84) and DIEA (0.50 mL, 2.9 mmol). The mixturewas heated to 160° C. for 40 min using microwave. The mixture wasconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (EtOAc/hex, gradient 1/1 to 2/1) to give3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide7 (589 mg, 70%) as a white solid. MS m/z 497 [M+H]⁺; ¹H NMR (300 MHz,CDCl₃) δ0.60 (m, 2H), 0.86 (m, 2H), 2.24 (s, 3H), 2.87 (m, 1H), 5.81(bs, 2H), 6.35 (bs, 1H), 7.25 (dd, J₁=J₂=7.8 Hz, 1H), 7.45 (d, J=8.1 Hz,1H), 7.69 (d, J=1.7 Hz, 1H), 7.80 (m, 3H), 7.89 (m, 1H), 8.00 (s, 1H)ppm.

Example 7 Preparation of{5-amino-1-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-1H-pyrazol-4-yl}-phenyl-methanone

A. N-Dimethylaminomethylene-4-methyl-3-nitro-benzamide

4-Methyl-3-nitro-benzamide 1 (10 g, 56 mmol) was suspended in 80 mL ofN,N-dimethylformamide dimethylacetal and was then heated to 95° C. for 2h. The red solution was allowed to cool to room temperature withstirring. After another 2 h, the resulting red precipitate was collectedon a fritted filter, and was washed three times with Et₂O to giveN-dimethylaminomethylene-4-methyl-3-nitro-benzamide 2 as a red solid(8.7 g, 66%). HPLC (4 minute gradient) t_(R) 1.76 min; MS m/z 236.0[M+H]⁺.

B. 3-(4-Methyl-3-nitro-phenyl)-4H-[1,2,4]triazole

To a solution of N-dimethylaminomethylene-4-methyl-3-nitro-benzamide 2(8.6 g, 37 mmol) in 250 mL of acetic acid was added dropwise anhydroushydrazine (4.7 mL, 180 mL). The now light orange solution was heated to95° C. for 1.5 h before allowing to cool and to stir at room temperaturefor 18 h. Acetic acid was removed in vacuo, and the residue waspartitioned between H₂O and EtOAc. The organic layer was washed twicewith saturated NaHCO₃ solution, then dried over MgSO₄. After filtrationand concentration in vacuo, the residue was triturated with warm EtOAc,and the resulting off-white solid was collected on a fitted filter togive 3-(4-methyl-3-nitro-phenyl)-4H-[1,2,4]triazole 3 (5.8 g, 77%). HPLC(4 minute gradient) t_(R) 1.82 min; MS m/z 205.1 [M+H]⁺; ¹H NMR (300MHz, DMSO-d₆)

8.57 (bs, 1H), 8.46 (s, 1H), 8.12 (d, J=7.9, 1H), 7.56 (d, J=7.9, 1H),2.5 (s, 3H) ppm; ¹³C NMR (DMSO-d₆, 125 MHz) δ 149.1, 133.5, 130.1,121.3, 19.5 ppm.

C. 2-Methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamine

3-(4-Methyl-3-nitro-phenyl)-4H-[1,2,4]triazole 3 (5.75 g, 28.2 mmol) wassuspended in 220 mL of ethanol with 2.35 mL (ca. 28.2 mmol) ofconcentrated aqueous HCl. Under nitrogen, 900 mg of 10% palladium onactivated carbon (dry) was added carefully. Hydrogen gas was bubbledthrough the reaction mixture via a balloon attached to a syringe needlefor 5 minutes. The reaction mixture was then stirred under an atmosphereof hydrogen gas maintained by a balloon at room temperature for 5 h. Thecatalyst was removed by filtration through a short pad a Celite. Thefiltrate was concentrated in vacuo, and the residue was neutralized withsaturated NaHCO₃ solution. The mixture was extracted with EtOAc sixtimes and the combined organic layers were dried over MgSO₄. Afterfiltration and concentration in vacuo, the residue was recrystallized inEtOAc to give 2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamine 4 (4.5 g,92%) as an off-white solid. HPLC (4 minute gradient) t_(R) 0.79 min; MSm/z 175.2 [M+H]⁺; ¹H NMR (300 MHz, MeOH-d₃)

8.10 (bs, 1H), 7.54 (s, 1H), 7.29 (m, 2H), 7.15 (d, J=7.6, 2 H), 2.23(s, 3H) ppm.

D. [2-Methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-hydrazine

2-Methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamine 4 (200 mg, 1.15 mmol,preparation) in dioxane (5 ml) and water (5 ml) at 0° C. was added conc.HCl (10 mL) followed by the addition of sodium nitrite (87 mg, 1.26mmol). The reaction mixture was stirred at 0° C. for 40 min then asolution of tin(II)chloride (481 mg, 2.59 mmol) in conc. HCl (1 mL) wasadded dropwise. The mixture was stirred for 2 hr at 0° C. which resultedin a white solid precipitate. The solid was collected by filtration andidentified as [2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-hydrazine 5(261 mg) which was used without further purification. HPLC (4 minutegradient) t_(R) 0.71 min; MS m/z 190.1 [M+H]⁺.

E.{5-Amino-1-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-1H-pyrazol-4-yl-phenyl-methanone

To a stirred solution of[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-hydrazine 5 (261 mg,estimated 1.15 mmol) in EtOH (25 ml) was added2-benzoyl-3-phenylamino-acrylonitrile 6 (285 mg, 1.15 mmol, preparation:Grothaus, J. Am. Chem. Soc. 58, 1334 (1936)) and the mixture was heatedto 65-70° C. for 12-16 hours. It was cooled to room temperature,concentrated to give crude product. The mixture was then purified byflash chromatography, eluting with 1:1 EtOAc/Hexanes to give{5-amino-1-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-1H-pyrazol-4-yl}-phenyl-methanone7 as a white solid (21 mg, 0.09 mmol, 8%). HPLC (4 minute gradient)t_(R) 1.89 min; MS m/z 345.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.40(d, 1H), 8.24 (bs, 1H), 8.14 (s, 1H), 8.12 (d, 2H), 7.34 (bs, 2H),7.92-7.85 (m, 4H), 2.49 (s, 3H) ppm; ¹³C NMR (DMSO-d₆, 500 MHz)

152.9, 142.2, 140.5, 137.1, 132.7 132.2, 129.4, 128.8, 127.6, 126.0,103.6, 18.1 ppm.

Example 8 Preparation of3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 3-[1,3]Dioxolan-2-yl-benzoic acid methyl ester

A mixture of 3-formyl-benzoic acid methyl ester 1 (6.09 g, 37.2 mmol),ethylene glycol (2.28 mL, 40.9 mmol) and p-toluenesulfonic acidmonohydrate (0.78 g, 4.09 mmol) was refluxed overnight with Dean-Starkapparatus. TLC plate showed that all the starting material hasdisappeared. Poured the reaction mixture into a mixture of cooledaqueous NaHCO₃ and EtOAc. The organic layer was separated and dried overNa₂SO₄. Filtered and concentrated to give the crude product that waspurified by silica gel chromatography (eluent: 8/1 hexane/ethylacetate). The desired 3-[1,3]dioxolan-2-yl-benzoic acid methyl ester 2was obtained as a colorless oil (6.41 g, 83%). ¹H NMR (300 MHz, CDCl₃)

3.92 (s, 3H), 4.01 (m, 2H), 4.13 (m, 2H), 5.85 (s, 1H), 7.46 (dd,J₁=J₂=7.7 Hz, 1H), 7.68 (dt, J₁=7.7 Hz, J₂=1.2 Hz, 1H), 8.05 (dt, J₁=7.7Hz, J₂=1.5 Hz, 1H), 8.16 (dd, J₁=J₂=1.5 Hz, 1H) ppm.

B. 3-(3-[1,3]Dioxolan-2-yl-phenyl)-3-oxo-propionitrile

To a mixture of acetonitrile (1.90 mL, 36.4 mmol) in THF (60 mL) wasadded LDA (1.8 M in THF, 33.9 mL) at −78° C. After stirring the mixturefor 20 min at −78° C., 3-[1,3]dioxolan-2-yl-benzoic acid methyl ester 2(6.06 g, 29.1 mmol) in THF (20 ml) was added all at once. The mixturewas stirred at −78° C. for 1.5 h and then warmed to 0° C. and stirredfor 1 h at this temperature. Saturated NH₄Cl was added to quench thereaction. The mixture was extracted with EtOAc three times. Organiclayers were combined and dried over Na₂SO₄. Filtration and concentrationin vacuo gave a residue that was purified by silica gel chromatography(CH₂Cl₂, then 20/1 CH₂Cl₂/ethyl acetate). The desired3-(3-[1,3]dioxolan-2-yl-phenyl)-3-oxo-propionitrile 3 was obtained as awhite solid (5.71 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ4.12 (m, 6H), 5.86(s, 1H), 7.55 (dd, J₁=J₂=7.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.92 (d,J=7.7 Hz, 1H), 8.01 (s, 1H) ppm.

C. 2-(3-[1,3]Dioxolan-2-yl-benzoyl)-3-phenylamino-acrylonitrile

The mixture of 3-(3-[1,3]dioxolan-2-yl-phenyl)-3-oxo-propionitrile 3(3.07 g, 15.0 mmol) and N,N′-diphenylformamidine (4.10 g, 21 mmol) intoluene was heated to reflux for 18 h. Concentration in vacuo gave aresidue that was purified by silica gel chromatography (hexanes/EtOAc,gradient from 3/1 to 2/1 then 1/1). The desired2-(3-[1,3]dioxolan-2-yl-benzoyl)-3-phenylamino-acrylonitrile 4 wasobtained as a yellow solid (3.88 g, 81%). ¹H NMR (300 MHz, CDCl₃) δ4.12(m, 4H), 5.92 (s, 1H), 7.26 (m, 4H), 7.47 (m, 3H), 7.65 (d, J=7.7 Hz,1H), 7.94 (dt, J₁=7.7 Hz, J₂=1.3 Hz, 1H), 8.05 (m, 2H) ppm.

D.3-[5-Amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A mixture of2-(3-[1,3]dioxolan-2-yl-benzoyl)-3-phenylamino-acrylonitrile 4 (0.20 g,0.62 mmol), N-cyclopropyl-3-hydrazino-4-methyl-benzamide,trifluoroacetic acid salt 8 (Example 6C, 0.20 g, 0.62 mmol) and DIEA(0.5 mL) in DMF (3 mL) was heated to 160° C. for 40 min using microwave.The mixture was then cooled down to room temperature and concentrated.The obtained residue was purified by silica gel chromatography (gradientfrom 1/4 Hexanes/EtOAc to 100% EtOAc). The desired3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide5 was obtained as an orange solid (0.26 g, 100%). MS m/z 433.2 [M+H]⁺;¹H NMR (300 MHz, CDCl₃)

0.60 (m, 2H), 0.86 (m, 2H), 2.24 (s, 3H), 2.87 (m, 1H), 4.11 (m, 4H),5.85 (m, 3H), 6.51 (bs, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.45 (dd, J₁=J₂=7.6Hz, 1H), 7.70 (m, 2H), 7.82 (m, 3H), 7.95 (s, 1H), 8.00 (s, 1H) ppm.

Example 9 Preparation of3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A mixture of3-[5-amino-4-(3-[1,3]dioxolan-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide5 (Example 8, 1.14 g, 2.6 mmol) was suspended in aqueous AcOH (10 mL,1.5 M in H₂O). Glacial AcOH was added dropwise until a clear solutionwas obtained. The reaction mixture was stirred at room temperatureovernight. Evaporation of the solvent under reduced pressure to give aresidue. Toluene and EtOAc were added and the mixture was concentratedagain to give the crude product that could be purified by silica gelchromatography (hexanes/EtOAc: 1/4). The desired3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide6 was obtained as a yellow foamy solid (0.91 g, 89%). MS m/z 389.1[M+H]⁺; ¹H NMR (300 MHz, CDCl₃)

0.61 (m, 2H), 0.85 (dd, J₁=6.9 Hz, J₂=12.4 Hz, 2H), 2.25 (s, 3H), 2.87(m, 1H), 5.95 (brs, 2H), 6.57 (brs, 1H), 7.44 (d, J=8.0 Hz, 1H),7.67-7.78 (m, 4H), 8.07 (s, 1H), 8.09 (d, J=1.3 Hz, 1H), 8.31 (s, 1H),10.12 (s, 1H) ppm.

Example 10 Preparation of3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

To a mixture of3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide6 (38 mg, 0.098 mmol) in methanol (3 mL) was added NaBH₄ (11 mg, 0.29mmol). The reaction mixture was stirred at room temperature for 1 h.Aqueous NaOH was added to quench the reaction and the mixture wasextracted with ethyl acetate. The organic layer was separated and washedwith water and saturated NaCl solution. The organic was then dried overNa₂SO₄, filtered and concentrated to give a residue that could bepurified by silica gel chromatography (eluent: 1/4 hexanes/EtOAc). Thedesired3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide7 was obtained as a white solid (22 mg, 58%). MS m/z 391.2 [M+H]⁺; ¹HNMR (300 MHz, CDCl₃)

0.56 (m, 2H), 0.82 (m, 2H), 2.22 (s, 3H), 2.82 (m, 1H), 4.75 (s, 2H),5.91 (brs, 2H), 6.75 (brs, 1H), 7.49 (m, 3H), 7.76 (m, 4H), 7.99 (s, 1H)ppm.

Example 11 Preparation of3-{5-amino-4-[3-(4-methyl-piperazin-1-ylmethyl)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

To a mixture of3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide6 (Example 9, 1.0 eq) and 1-methyl-piperazine (1.09 eq) in equal volumeof 1,2-dichloroethane and dichloromethane was added AcOH (0.96 eq)Sodium triacetoxyborohydride (1.5 eq) was then added. The reactionmixture was stirred at room temperature for 2 h. Aqueous NaOH was addedto quench the reaction and the mixture was extracted with ethyl acetate.The organic layer was separated and washed with water and saturated NaClsolution. The organic layer was then dried over Na₂SO₄, filtered andconcentrated to give a residue that could be purified by silica gelchromatography (eluent: 9/1 CH₂Cl₂/methanol then 9/1/0.05CH₂Cl₂/MeOH/NH₃H₂O). Yield 67%. MS m/z 473.3 [M+H]⁺; ¹H NMR (300 MHz,CDCl₃)

0.61 (m, 2H), 0.86 (m, 2H), 2.26 (s, 3H), 2.30 (s, 3H), 2.52 (brs, 8H),2.90 (m, 1H), 3.60 (s, 2H), 5.87 (brs, 1H), 6.30 (brs, 2H), 7.45 (m,3H), 7.70 (m, 2H), 7.83 (m, 3H) ppm.

Example 12 Preparation of3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 11 except morpholine was used in placeof 1-methyl-piperidine. Yield 45%. MS m/z 460.2 [M+H]⁺; ¹H NMR (300 MHz,CDCl₃)

0.61 (m, 2H), 0.87 (m, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 2.49 (m, 4H),2.90 (m, 1H), 3.59 (s, 2H), 3.72 (t, J=4.4 Hz, 2H), 5.85 (brs, 2H), 6.35(brs, 1H), 7.45 (m, 3H), 7.71 (m, 2H), 7.83 (m, 3H) ppm.

Example 13 Preparation of3-{5-Amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

A. 3-(2-Morpholin-4-yl-ethoxy)-benzoic acid ethyl ester

Potassium carbonate (6.2 g, 45 mmol) was added to a DMF solution (100mL) of ethyl 3-hydroxybenzoate 1 (3.32 g, 20 mmol),4-(2-chloroethyl)-morpholine hydrochloride (5.58 g, 30 mmol) and18-crown-6 (20 mg). The mixture was stirred at 100° C. for 20 hr.Solvent was removed in vacuo and the residue was suspended in ethylacetate. The organic layer was washed by saturated NaHCO₃ solution andthen brine, and was dried over sodium sulfate. Solvent was evaporated toyield the product 3-(2-morpholin-4-yl-ethoxy)-benzoic acid ethyl ester 2as a light yellow oil (5.3 g, 95%). HPLC (4 minute gradient) t_(R) 1.47min; MS m/z 280.2 [M+H]⁺.

B. 3-[3-(2-Morpholin-4-yl-ethoxy)-phenyl]-3-oxo-propionitrile

Lithium diisopropylamide (16.4 mL, 29.6 mmol, 1.8M solution inheptane/tetrahydrofuran/ethylbenzene) was added dropwise to the solutionof acetonitrile (1.2 g, 29.6 mmol) in dry tetrahydrofuran (20 mL) at−78° C. in nitrogen atmosphere. After stirring the reaction mixture for30 min, a solution of 3-(2-morpholin-4-yl-ethoxy)-benzoic acid ethylester 2 (5.5 g, 19.7 mmol) in dry tetrahydrofuran (20 mL) was addeddropwise and stirred at −78° C. for 1 hr. Water was added and theaqueous layer was separated and acidified with dilute hydrochloric acidto pH 7. The product was extracted into ethyl acetate. The organic layerwas washed with brine and then dried over sodium sulfate. The solventwas removed in vacuo to give3-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-3-oxo-propionitrile 3 as a lightyellow oil (4.8 g). HPLC (4 minute gradient) t_(R) 1.11 min; MS m/z275.2 [M+H]⁺.

C. 2-[3-(2-Morpholin-4-yl-ethoxy)-benzoyl]-3-phenylamino-acrylonitrile

A mixture of 3-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-3-oxo-propionitrile3 (4.8 g, 17.5 mmol) and N,N-diphenylformamidine (1.2 g, 24.5 mmol) indry toluene (100 mL) was heated at 110° C. for 3 hr under a nitrogenatmosphere. Solvent was removed and the oily residue was subjected tosilica gel column chromatography (gradient 100% EtOAc to 100/10/1EtOAc/MeOH/Et₃N) to yield2-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-3-phenylamino-acrylonitrile 4light yellow solid (3.1 g, 47%). HPLC (4 minute gradient) t_(R) 2.04min; MS m/z 378.2 [M+H]⁺.

D.3-{5-Amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-pyrazol-1-yl}-4-methyl-benzoicacid

2-[3-(2-Morpholin-4-yl-ethoxy)-benzoyl]-3-phenylamino-acrylonitrile 4(189 mg, 0.5 mmol) and 3-hydrazino-4-methyl-benzoic acid hydrochloride 7(Example 3A 152 mg, 0.75 mmol) were suspended in N,N-dimethylformamide(5 mL) and heated at 160° C. using microwave for 30 min. Solvent wasevaporated and the residue was subjected to column chromatography(EtOAc˜MeOH). Product3-{5-amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-pyrazol-1-yl}-4-methyl-benzoicacid 5 was obtained as a light yellow solid (200 mg). HPLC (4 minutegradient) t_(R) 1.60 min; MS m/z 451.2 [M+H]⁺.

E.3-{5-Amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

A mixture of3-{5-amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-pyrazol-1-yl}-4-methyl-benzoicacid 5 (400 mg, 0.89 mmol), cyclopropylamine (0.89 mmol), EDCI (340 mg,1.78 mmol), HOBt (272 mg, 1.78 mmol) and diisopropylethylamine (459 mg,3.56 mmol) in dry N,N-dimethylformamide (10 mL) was stirred at roomtemperature for 18 h. Solvent was evaporated and the residue wassuspended in EtOAc and washed by water, saturated NaHCO₃ solution andbrine. The organic layer was dried over sodium sulfate. Product3-{5-amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl}-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide6 was obtained as a light yellow solid (45 mg, 10%) after purificationby column chromatography (100/10/1 EtOAc/MeOH/Et₃N). HPLC (4 minutegradient) t_(R) 1.69 min; MS m/z 490.24 [M+H]⁺.

Example 14 Preparation of3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 3-Benzyloxy-benzoic acid ethyl ester

K₂CO₃ (6.9 g, 50 mmol) and 18-crown-6 were added to a solution of3-hydroxy-benzoic acid ethyl ester 1 (8.3 g, 50 mmol) in acetone (100mL) and the mixture was stirred at room temperature for 18 h. Solid wasremoved by filtration. Filtrate was concentrated in vacuo to give3-benzyloxy-benzoic acid ethyl ester 2 as a colorless liquid.

B. 3-(3-Benzyloxy-phenyl)-3-oxo-propionitrile

LDA (1.8 M, 100 mmol, 56 mL) was added to a solution of acetonitrile(4.1 g, 100 mmol) in THF (100 mL, dry) at −78° C. under nitrogen. Themixture was stirred at −78° C. for 30 min. A solution of3-benzyloxy-benzoic acid ethyl ester 2 in 50 mL anhydrous THF was thenadded dropwise to the reaction mixture. The mixture was stirred at −78°C. for 1 h before water was added. The organic phase was separated. Theaqueous phase was acidified by hydrochloride acid until pH ˜2, and wasextracted by EtOAc. THF and EtOAc layers were combined and washed bywater, brine, dried over Na₂SO₄. Solvent was removed in vacuo and thesolid residue was triturate with Et₂O and dried in vacuo. The desiredproduct 3-(3-benzyloxy-phenyl)-3-oxo-propionitrile 3 was obtained as alight brown solid (11.0 g, 87%).

C. 2-(3-Benzyloxy-benzoyl)-3-dimethylamino-acrylonitrile

N,N-Dimethylformamide dimethyl acetal (10 mL) was added to the solutionof 3-(3-benzyloxy-phenyl)-3-oxo-propionitrile 3 (2.5 g, 10 mmoL) in DMF(20 mL, dry) and the mixture was stirred at 100° C. for 3 hr. Solventwas removed and the residue was purified by silica gel columnchromatography (EtOAc as eluent). Product2-(3-benzyloxy-benzoyl)-3-dimethylamino-acrylonitrile 4 was obtained asa light yellow solid (2.6 g, 90%).

D.3-[5-Amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

2-(3-Benzyloxy-benzoyl)-3-dimethylamino-acrylonitrile 4 (147 mg, 0.5mmol) and N-cyclopropyl-3-hydrazino-4-methyl-benzamide, trifluoroaceticacid salt 8 (Example 6C, 240 mg, 0.75 mmol) were dissolved in DMF (5 mL)and was heated at 160° C. in microwave oven for 30 min. Solvent wasremoved and the residue was purified by column (3:1 EtOAc/hexanes).Product3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide6 was obtained as a light yellow solid (120 mg, 52%).

Example 15 Preparation of3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

3-[5-Amino-4-(3-benzyloxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide6 (200 mg, 0.43 mmol) was dissolved in MeOH (10 mL). Catalyst 10%palladium on activated carbon (dry) was added and was stirred in anatmosphere of hydrogen for 2 h. The catalyst was removed by filtrationand solvent was removed in vacuo. Product3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide7 was obtained as a light yellow solid (140 mg, 87%).

Example 16 Preparation of3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 2-(4-Methyl-benzoyl)-3-phenylamino-acrylonitrile

A mixture of 4-toluoylacetonitrile 1 (4.0 g, 25 mmol) andN,N-diphenylformamidine (4.9 g, 25 mmol) in dry toluene (50 mL) washeated at 85° C. for 16 h under nitrogen. The mixture was cooled to roomtemperature and 170 mL of hexanes was added. A yellow precipitate wasformed after the mixture was stirred at room temperature for 5 minutes.The solid was collected of a fritted flask, and was washed with hexanesto give pure 2-(4-methyl-benzoyl)-3-phenylamino-acrylonitrile 2 (4.5 g,68%). ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=13.0, 1H), 7.86 (d, J=7.9, 2H), 7.42 (t, J=7.4, 1H), 7.28-7.25 (m, 3H), 7.19 (d, J=7.6, 1H), 2.41(s, 3H) ppm.

B.3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A mixture of 2-(4-methyl-benzoyl)-3-phenylamino-acrylonitrile 2 (205 mg,0.78 mmol), N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroaceticacid salt 7 (Example 6C, 250 mg, 0.78 mmol) and diisopropylethylamine(0.14 mL, 0.78 mmol) in 8 mL of ethanol was heated at 65° C. in for 18h. Solvent was removed and the residue was purified by silica gel columnchromatography (EtOAc/hexanes, gradient from 1/3 to 3/1). The productcan be further purified by trituration with Et₂O to give3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide3 as a white solid (64 mg, 22%). HPLC (4 minute gradient) t_(R) 2.26min; MS m/z 375.2 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (d, J=4.0,1H), 7.93 (d, J=8.0, 1H), 8.51 (d, J=4.0, 1H), 7.83 (bs, 1H), 7.82 (s,1H), 7.70 (d, J=7.9, 2 H), 7.53 (d, J=8.0, 1H), 7.35 (d, J=7.9, 2 H),6.95 (bs, 2H), 2.86 (m, 1H), 2.40 (s, 3H), 2.14 (s, 3H), 0.68 (m, 2H),0.56 (m, 2H); ¹³C NMR (300 MHz, DMSO-d₆) δ 187.4, 166.0, 151.9, 141.3,141.1, 139.2, 136.9, 135.6, 133.0, 131.2, 129.1, 128.3, 128.0, 126.5,102.6, 23.1, 21.0, 17.2, 5.6 ppm.

Example 17 Preparation of3-(5-amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

A. 3-(5-Amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

A mixture of 3-amino-N-cyclopropyl-4-methyl-benzamide 1 (380 mg, 2.0mmol) in 2.0 mL of triethyl orthoformate was stirred at 120° C. inmicrowave for 20 minutes. The solvent was removed under reducedpressure. The residue was dissolved in 5 mL of acetic acid and then wasadded aminomalononitrile p-toluenesulfonate (506 mg, 2.0 mmol) andsodium acetate (164 mg, 2.0 mmol). The reaction mixture was stirred atroom temperature overnight. The mixture was diluted with 20 mL of waterand then its pH was adjusted to 8.0 by aqueous NaOH. The resultingmixture was extracted with EtOAc (3×50 mL). The combined organic layerswere washed with water (10 mL) and brine (10 mL), dried over MgSO₄,filtered and concentrated in vacuo evaporated. The residue was purifiedby silica gel column chromatography (10/1, methylene chloride:methanol)to give3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 3 asa colorless solid (170 mg, 30%). HPLC (4 minute gradient) t_(R)=1.39min; MS m/z 282 [M+H].

B. 3-(5-Amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

To a solution of3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 3(56.4 mg, 0.2 mmol) in dry THF (10 ml) under nitrogen was addedphenylmagnesium bromide (1M, 1 mL) at room temperature. After 1 h, HClsolution (3N, 10 ml) was added and the mixture was stirred overnight.The solution was neutralized with dilute aqueous NaOH. The mixture wasextracted with ethyl acetate (100 mL×2), washed with water and driedover Na₂SO₄. Evaporation of the solvent gave a residue which waspurified by HPLC to give3-(5-Amino-4-benzoyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide asa while solid (56 mg, 78%). LCMS (4 minute gradient) t_(R)=2.07 min; MSm/z 361.17 [M+H]

Example 18 Preparation of3-(5-Amino-4-cyclohexanecarbonyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 17 except cyclohexylmagnesium bromidewas used in place of phenyl magnesium bromide. HPLC (4 minute 10-90gradient) t_(R) 2.01 min; MS m/z 367.29 [M+H]⁺.

Example 19 Preparation of3-(5-Amino-4-cyclopentanecarbonyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 17 except cyclopentylmagnesium bromidewas used in place of phenyl magnesium bromide. HPLC (4 minute 10-90gradient) t_(R) 1.92 min; MS m/z 353.22 [M+H]⁺.

Example 20 Preparation of3-(5-Amino-4-phenylacetyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 17 except benzylmagnesium bromide wasused in place of phenyl magnesium bromide. HPLC (4 minute 10-90gradient) t_(R) 2.14 min; MS m/z 375.20 [M+H]⁺.

Example 21 Preparation of3-[5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A.3-[5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-imidazole-4-carbonyl]-benzoicacid

To a solution of 3-iodobenzoic acid tert-butyl ester (4.6 g) in THF (20mL) at −40° C. under N₂ was added cyclohexylmagnesium chloride (2M inTHF, 8.5 mL). The solution was kept at −40° C. to 0° C. for 20 min.,when 3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamidewas added and the reaction was kept at rt for 1 h. Then HCl (4 M, 10 mL)was added and the mixture was heated at 40 to 45° C. overnight. Themixture was neutralized with K₂CO₃ solution and extracted with EtOAc(2×100 mL) and the combined organics dried over Na₂SO₄, andconcentrated. Purification of the crude product by column chromatography(EtOAc: MeOH=6:1) gave the desired product (0.46 g).

B3-[5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A solution of acid 4 (160 mg), EDCI (90 mg), and N-hydroxysucinimide (53mg) in DMF (2 mL) was reacted at rt overnight. Water (12 ml) was addedand the solution was extracted with EtOAc (15 mL×2), dried over Na₂SO₄.Evaporation of solvent gave a residue, into which EtOAc (4 mL) and2-propylamine (1.2 eq) was added. The reaction was kept at rt for 1 h.,then concentrated and the crude product purified by columnchromatography to give the desired product (yield: 80%). HPLC (4 minutegradient) t_(R)=2.00 min; MS m/z 446.19 [M+H]⁺.

Example 22 Preparation of3-{5-Amino-4-[3-(2-dimethylamino-ethylcarbamoyl)-benzoyl]-imidazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except 2-dimethylaminoethylamine wasused in place of isopropylamine. HPLC (4 minute 10-90 gradient) t_(R)2.18 min; MS m/z 475.15 [M+H]⁺.

Example 23 Preparation of3-[5-Amino-4-(3-ethylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except ethylamine was used in placeof isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.70 min; MS m/z432.18 [M+H]⁺.

Example 24 Preparation of3-[5-Amino-4-(3-methylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except methylamine was used in placeof isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.61 min; MS m/z418.15 [M+H]⁺.

Example 25 Preparation of3-[5-Amino-4-(3-cyclopropylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except cyclopropylamine was used inplace of isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.74 min;MS m/z 444.14 [M+H]⁺.

Example 26 Preparation of3-[5-Amino-4-(3-cyclopentylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except cyclopentylamine was used inplace of isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.95 min;MS m/z 472.24 [M+H]⁺.

Example 27 Preparation of3-[5-Amino-4-[3-(morpholine-4-carbonyl)-benzoyl]-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except morpholine was used in placeof isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.67 min; MS m/z474.17 [M+H]⁺.

Example 28 Preparation of3-[5-Amino-4-[3-(cyclopropylmethyl-carbamoyl)-benzoyl]-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except cyclopropylmethylamine wasused in place of isopropylamine. HPLC (4 minute 10-90 gradient) t_(R)1.86 min; MS m/z 458.23 [M+H]⁺.

Example 29 Preparation of3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 4-bromo-tetrahydro-pyran

Tetrahydro-4H-pyran-4-ol (1.0 g, 10 mmol), carbon tetrabromide (3.6 g,11 mmol) and triphenylphosphine (3.1 g, 12 mmol) were dissolved inCH₂Cl₂ (25 mL) and stirred at room temperature overnight. The crudereaction mixture was concentrated then purified by flash chromatographyon silica gel (EtOAc:Hexanes=1:20), and the product was obtained as acolorless oil (1.4 g, 87%).

B.3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A solution of 4-bromo-tetrahydro-pyran (0.82 g, 5 mmol) in dry THF (10mL) was added dropwise to the suspension of magnesium (132 mg, 5.5 mmol)and iodine (25 mg) in dry THF (20 mL) at 50° C. under N₂. The mixturewas stirred for 30 min after addition at 50° C., then cooled to roomtemperature. Then a THF (10 mL) solution of3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (90mg, 0.32 mmol) was added to the reaction mixture and it was stirred atroom temperature for 3 h then quenched with HCl (2N) and stirred at roomtemperature overnight. The pH of the solution was adjusted pH ˜8 withsaturated aqueous K₂CO₃ was and it was extracted with EtOAc. The organiclayer was washed by water and brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by column chromatography onsilical gel (EtOAc˜EtOAc:MeOH:Et₃N=100:10:1), and the product wasobtained as a beige solid (35 mg, 30%). HPLC (4 minute gradient)t_(R)=3.05 min; MS m/z 369.18 [M+H]⁺.

Example 30 Preparation of3-(5-amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

A. 2-Benzoyl-3,3-bis-methylsulfanyl-acrylonitrile

To a stirred solution of benzoylacetonitrile 1 (7.50 g, 51.7 mmol) inTHF (100 ml) at 0° C. was added dry sodium hydride (2.61 g, 103 mmol).The resulting suspension was stirred at 0° C. for 45 min before carbondisulfide (2.39 ml, 54.8 mmol) was added. The reaction was then stirredat room temperature for 2 h. The resulting red solution was cooled to 0°C., and iodomethane (6.75 ml, 109 mmol) was added. The mixture wasstirred at room temperature for 18 h. Solvent was removed in vacuo. Theresidue was diluted in ether and was washed with brine. The aqueouslayer was extracted twice with ether. The combined organic layers werewashed twice with 5% sodium thiosulfate, and then brine. The organiclayer was dried over MgSO₄, filtered and concentrated to give2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 as a yellow powder (9.5g, 74%). The product was used in the next step without furtherpurification.

B.3-(5-Amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

Sodium (317 mg, 13.8 mmol) was added to methanol (10 ml) at 0° C. Afterall of the sodium was consumed, this solution of sodium methoxide wasadded to a stirred solution of2-benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (3.12 g, 12.5 mmol) indioxane (30 ml) at 0° C. The reaction was warmed to room temperature andthen heated to 80° C. for 3 h. The dark red solution was cooled to roomtemperature and was added to a solution ofN-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt(4.00 g, 12.5 mmol) and diisopropylethylamine (2.18 ml, 12.5 mmol) indioxane (15 ml). The mixture was heated to 85° C. for another 6 h. Thesolvent was removed in vacuo. The residue was diluted in saturatedNaHCO₃ solution and was extracted three times with EtOAc. Combinedorganic layers were dried over MgSO₄, filtered and concentrated. Thecrude product was purified by flash chromatography (SiO₂, gradient of 75to 90% EtOAc/hexanes) and recrystallization from EtOAc to give thedesired3-(5-amino-4-benzoyl-3-methoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide3 as a white solid (950 mg, 19%). HPLC (4 minute 10-90 gradient) t_(R)2.33 min; MS m/z 391.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.50 (d,J=3.4, 1H), 7.91 (d, J=7.9, 1H), 7.85 (s, 1H), 7.61 (d, J=6.9, 2 H),7.41-7.62 (m, 4H), 7.00 (bs, 2H), 3.66 (s, 3H), 2.87 (m. 1H), 2.20 (s,3H), 0.70 (m, 2H), 0.85 (m, 2H) ppm; ¹³C NMR (DMSO-d₆, 125 MHz) δ 188.1,166.0, 159.5, 152.8, 140.1, 139.5, 135.5, 132.9, 131.1, 130.6, 128.1,128.0, 127.4, 126.8, 91.0, 55.2, 23.0, 15.1, 5.6 ppm.

Example 31 Preparation of3-(5-amino-4-benzoyl-3-ethoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

Ethanol (0.47 ml, 8.0 mmol) was added to a suspension of dry sodiumhydride (41 mg, 1.6 mmol) in dioxane (2 ml). The mixture was stirred atroom temperature for 10 min.2-Benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) wasadded, and the mixture was stirred at 85° C. for 2.5 h. The mixture wascooled to room temperature. N-Cyclopropyl-3-hydrazino-4-methyl-benzamidetrifluoroacetic acid salt (0.26 g, 0.80 mmol) was added and the reactionwas heated to 85° C. for another 3 h. Solvents were removed in vacuo.The residue was diluted in saturated NaHCO₃ solution and was extractedthree times with EtOAc. Combined organic layers were dried over MgSO₄,filtered and concentrated. The crude product was purified by flashchromatography (SiO₂, gradient of 75 to 85% EtOAc/hexanes). The productwas further purified by washing with a warm mixture of EtOAc and hexanesto give the desired3-(5-amino-4-benzoyl-3-ethoxy-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide4 as a white solid (27 mg, 8.3%). HPLC (4 minute 10-90 gradient) t_(R)2.37 min; MS m/z 405.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.49 (d,J=4.0, 1H), 7.90 (d, J=8.0, 1H), 7.85 (s, 1H), 7.62 (d, J=7.1, 2 H),7.50 (d, J=7.5, 2 H), 7.41-7.45 (m, 2H), 6.99 (bs, 2H), 4.05 (q, J=7.0,2 H), 2.87 (m. 1H), 2.19 (s, 3H), 1.09 (t, J=7.0, 3 H), 0.69 (m, 2H),0.58 (m, 2H) ppm; ¹³C NMR (DMSO-d₆, 125 MHz) δ 188.2, 166.0, 158.9,152.6, 140.0, 139.5, 135.5, 132.9, 131.1, 130.6, 128.1, 127.2, 126.7,91.2, 63.4, 23.0, 17.3, 14.2, 5.6 ppm.

Example 32 Preparation of3-[5-amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Dry sodium hydride (21 mg, 0.84 mmol) was added to a solution of2-methoxyethanol (0.63 ml, 8.0 mmol) in dioxane (2 ml) at 0° C. Themixture was stirred at room temperature for 30 min.2-Benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) wasadded, and the mixture was stirred at 85° C. for 4 h. The mixture wascooled to room temperature. N-Cyclopropyl-3-hydrazino-4-methyl-benzamidetrifluoroacetic acid salt (0.26 g, 0.80 mmol), followed bydiisopropylethylamine (0.14 ml, 0.80 mmol), was added and the reactionwas heated to 85° C. for another 11 h. Solvents were removed in vacuo.The residue was diluted in saturated NaHCO₃ solution and was extractedthree times with EtOAc. Combined organic layers were dried over MgSO₄,filtered and concentrated. The crude product was purified by flashchromatography (SiO₂, gradient of 70 to 90% EtOAc/hexanes). The productwas further purified by washing with a warm mixture of EtOAc and hexanesto give the desired3-[5-amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide5 as a white solid (60 mg, 17%). HPLC (4 minute 10-90 gradient) t_(R)2.17 min; MS m/z 435.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.47 (s, 1H),7.89 (d, J=7.9, 1H), 7.83 (s, 1H), 7.64 (d, J=7.4, 2 H), 7.49 (d, J=7.7,2 H), 7.40-7.43 (m, 2H), 6.99 (bs, 2H), 4.12 (m, 2H), 3.42 (m, 2H), 3.12(s, 3H), 2.86 (m, 1H), 2.07 (s, 3H), 0.69 (m, 2H), 0.56 (m, 2H) ppm.

Example 33 Preparation of3-[5-amino-4-benzoyl-3-(2-benzyloxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Dry sodium hydride (21 mg, 0.84 mmol) was added to a solution of2-benzyloxyethanol (1.1 ml, 8.0 mmol) in dioxane (2 ml) at 0° C. Themixture was stirred at room temperature for 35 min.2-Benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) wasadded, and the mixture was stirred at 80° C. for 2.5 h. The mixture wascooled to room temperature. N-Cyclopropyl-3-hydrazino-4-methyl-benzamidetrifluoroacetic acid salt (0.26 g, 0.80 mmol) was added and the reactionwas heated to 80° C. for another 8.5 h. After the reaction mixture wascooled to room temperature, solvents were removed in vacuo. The residuewas diluted in saturated NaHCO₃ solution and was extracted three timeswith EtOAc. Combined organic layers were dried over MgSO₄, filtered andconcentrated. The crude product was purified by flash chromatography(SiO₂, gradient of 60 to 85% EtOAc/hexanes). The product was furtherpurified by washing with warm EtOAc to give the desired3-[5-amino-4-benzoyl-3-(2-benzyloxy-ethoxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide6 as an off-white solid (74 mg, 18%). HPLC (4 minute 10-90 gradient)t_(R) 2.57 min; MS m/z 511.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.49(d, J=4.0, 1H), 7.90 (d, J=8.0, 1H), 7.85 (s, 1H), 7.66 (d, J=7.1, 2 H),7.49 (m, 2H), 7.27-7.40 (m, 5H), 7.22 (d, J=6.7, 2 H), 7.02 (bs, 2H),4.34 (s, 2H), 4.19 (m, 2H), 3.57 (m, 2H), 2.87 (m, 1H), 2.17 (s, 3H),0.69 (m, 2H), 0.59 (m, 2H) ppm.

Example 34 Preparation of4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester

Dry sodium hydride (41.0 mg, 1.60 mmol) was added to a solution of4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 7 (0.565 g, 2.81mmol) in dioxane (2 ml) at 0° C. The mixture was stirred at roomtemperature for 45 min. 2-Benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2(0.20 g, 0.80 mmol) was added, and the mixture was stirred at 65° C. for4 h. The mixture was cooled to room temperature.N-Cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt(0.26 g, 0.80 mmol) was added and the reaction was heated to 80° C. foranother 3 h. After the reaction mixture was cooled to room temperature,solvents were removed in vacuo. The residue was diluted in saturatedNaHCO₃ solution and was extracted three times with EtOAc. Combinedorganic layers were dried over MgSO₄, filtered and concentrated. Thecrude product was purified by flash chromatography (SiO₂, gradient of 65to 85% EtOAc/hexanes). The product was further purified by washing thewith warm EtOAc to give the desired4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester 8 as an off-white solid (70 mg, 16%). HPLC (4minute 10-90 gradient) t_(R) 2.63 min; MS m/z 559.9 [M+H]⁺; ¹H NMR(DMSO-d₆, 300 MHz) δ 8.49 (d, J=3.6, 1H), 7.90 (d, J=8.1, 1H), 7.84 (s,1H), 7.59 (d, J=7.7, 2 H), 7.40-7.51 (m, 4H), 6.99 (bs, 2H), 4.75 (m,1H), 3.18 (m, 2H), 2.99 (m, 2H), 2.87 (m, 1H), 2.19 (s, 3H), 1.68 (m,2H), 1.43 (m, 2H), 1.37 (s, 9H), 0.71 (m, 2H), 0.58 (m, 2H) ppm.

Example 35 Preparation of3-[5-amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide,trifluoroacetate salt

To a solution of4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester 8 (5.0 mg, 0.0089 mmol) in dichloromethane (2.0ml) was added trifluoroacetic acid (0.5 ml). The mixture was stirred atroom temperature for 3 h. Volatiles were removed in vacuo and theresidue was washed with ether and a small amount of EtOAc to give thedesired3-[5-amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide,trifluoroacetate salt 9 as a white solid (3.0 mg, 59%). HPLC (4 minute10-90 gradient) t_(R) 1.75 min; MS m/z 460.1 [M+H]⁺; ¹H NMR (DMSO-d₆,300 MHz) δ 8.50 (d, J=4.0, 1H), 8.33 (bs, 2H), 7.90 (d, J=8.0, 1H), 7.83(s, 1H), 7.62 (d, J=7.0, 2 H), 7.44-7.52 (m, 4H), 7.03 (bs, 2H), 4.82(m, 1H), 2.97 (m, 2H), 2.85 (m, 1H), 2.73 (m, 2H), 2.27 (s, 3H), 1.91(m, 2H), 1.73 (m, 2H), 0.71 (m, 2H), 0.57 (m, 2H) ppm.

Example 36 Preparation of3-(5-amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

To a solution of benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.218g, 0.874 mmol) in ethanol (5 ml) was addedN-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt(0.243 g, 0.874 mmol) and diisopropylethylamine (0.152 ml, 0.874 mmol).The mixture was heated to 65° C. for 18 h. The mixture was cooled toroom temperature. Solvents were removed in vacuo. The residue wasdiluted in saturated NaHCO₃ solution and was extracted three times withEtOAc. Combined organic layers were dried over MgSO₄, filtered andconcentrated. The crude product was purified by flash chromatography(SiO₂, gradient of 65 to 100% EtOAc/hexanes). The product was furtherpurified by washing with a warm mixture of EtOAc and hexanes to give thedesired3-(5-amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide10 as an off-white solid (57 mg, 16%). HPLC (4 minute 10-90 gradient)t_(R) 2.34 min; MS m/z 407.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.50(d, J=4.0, 1H), 7.93 (dd, J=1.2, 7.9, 1H), 7.86 (s, 1H), 7.45-7.57 (m,6H), 6.85 (bs, 2H), 2.88 (m, 1H), 2.23 (s, 3H), 2.18 (s, 3H), 0.69 (m,2H), 0.58 (m, 2H) ppm; ¹³C NMR (DMSO-d₆, 125 MHz) δ 189.3, 165.9, 152.8,148.0, 140.4, 139.3, 135.4, 132.9, 131.2, 130.6, 128.4, 128.1, 127.2,126.6, 102.0, 23.0, 17.3, 13.4, 5.6 ppm.

Example 37 Preparation of3-(5-amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

To a suspension of3-(5-amino-4-benzoyl-3-methylsulfanyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide10 (40 mg, 0.098 mmol) in dichloromethane (1 ml) was added3-chloroperoxybenzoic acid (70-75%, 53 mg, 0.22 mmol). The resultingsolution was stirred at room temperature for 2 h, and then stored at 4°C. overnight. Upon warming to room temperature, the product began toprecipitate. The white solid was collected on a fitted funnel and waswashed with dichloromethane and ether to give the desired3-(5-amino-4-benzoyl-3-methanesulfonyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide11 (27 mg, 63%). HPLC (4 minute 10-90 gradient) t_(R) 1.98 min; MS m/z439.08 [M+H]; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.53 (d, J=3.7, 1H), 7.97 (d,J=8.1, 1H), 7.92 (s, 1H), 7.76 (d, J=7.2, 1H), 7.48-7.64 (m, 5 H), 6.30(bs, 2H), 3.29 (s, 3H), 2.88 (m, 1H), 2.17 (s, 3H), 0.69 (m, 2H), 0.58(m, 2H) ppm.

Example 38 Preparation of5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylicacid amide

To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylamide 12 (100 mg,0.574 mmol) in ethanol (5 ml) was addedN-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt(0.183 g, 0.574 mmol) and diisopropylethylamine (0.100 ml, 0.574 mmol).The mixture was heated to 65° C. for 18 h. The mixture was cooled toroom temperature. Solvents were removed in vacuo. EtOAc was added to theresidue and a solid precipitated. The solid was collected on a fittedfunnel and was washed with EtOAc and ether to give the desired5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylicacid amide 13. HPLC (4 minute 10-90 gradient) t_(R) 1.98 min; MS m/z439.08 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz) δ 8.47 (d, J=3.7, 1H), 7.90 (d,J=7.9, 1 H), 7.78 (s, 1H), 7.49 (d, J=8.0, 1H), 6.81 (bs, 2H), 6.30 (s,2H), 2.86 (m, 1H), 2.45 (s, 3H), 2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m,2H) ppm.

Example 39 Preparation of5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methanesulfonyl-1H-pyrazole-4-carboxylicacid amide

To a suspension of5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylicacid amide 13 (100 mg, 0.289 mmol) in dichloromethane (3 ml) was added3-chloroperoxybenzoic acid (70-75%, 157 mg, 0.637 mmol). The resultingclear solution was stirred at room temperature for 16 h. SaturatedNaHCO₃ solution was added and the mixture was vigorously stirred for fmin. The resulting suspension was filtered on a fritted funnel, and thecollected solid was washed three times with H₂O, and three times withether to give the desired5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methanesulfonyl-1H-pyrazole-4-carboxylicacid amide 14 as a white solid (87 mg, 80%). HPLC (4 minute 10-90gradient) t_(R) 1.66 min; MS m/z 378.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 500 MHz)δ 8.49 (s, 1H), 7.95 (d, J=7.6, 1H), 7.83 (s, 1H), 7.53 (d, J=7.8, 1H),7.46 (bs, 2H), 6.74 (bs, 2H), 3.40 (s, 3H), 2.84 (m, 1H), 2.09 (s, 3H),0.68 (m, 2H), 0.55 (m, 2H) ppm.

Example 40 Preparation of5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylicacid ethyl ester

To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was addedN-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt(0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol).The mixture was heated to 65° C. for 2 h. The mixture was cooled to roomtemperature. Solvents were removed in vacuo. EtOAc and ether was addedto the residue and a solid precipitated. The solid was collected on aflitted funnel and was washed with EtOAc and ether to give the desired5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylicacid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90gradient) t_(R) 2.18 min; MS m/z 375.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 8.47 (d, J=3.7, 1H), 7.90 (d, J=7.9, 1H), 7.78 (s, 1H), 7.49 (d,J=8.0, 1 H), 6.81 (bs, 2H), 6.30 (s, 2H), 2.86 (m, 1H), 2.45 (s, 3H),2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m, 2H) ppm.HPLC (4 minute 10-90gradient) t_(R) 1.66 min; MS m/z 378.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 300 MHz)δ 8.50 (d, J=2.6, 1H), 7.92 (d, J=7.9, 1 H), 7.81 (s, 1H), 7.51 (d,J=7.9, 1H), 6.24 (bs, 2H), 4.22 (q, J=6.6, 2 H), 2.88 (m, 1H), 2.35 (s,3H), 2.14 (s, 3H), 1.29 (t, J=6.7, 3 H), 0.72 (m, 2H), 0.58 (m, 2H) ppm;¹³C NMR (DMSO-d₆, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8,132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm.

Example 41 Preparation of3-[5-Amino-4-(3-chlorobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 2-(3-Chlorobenzoyl)-3-phenylaminoacrylonitrile

A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq)and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluenewas stirred at room temperature for 2 h then heated to 100° C.overnight. The solution was cooled and diluted with hexanes. Theresulting solid was filtered and dried to provide the desired product(566 mg, 75%). HPLC (4 minute 10-95 gradient) t_(R) 2.97 min; MS m/z283.2 [M+H]⁺; ¹H NMR (CDCl₃), δ 8.06 (d, J=13.2 Hz, 1H), 7.85 (m, 2H),7.46 (m, 4H), 7.27 (m, 4H) ppm.

B.3-[5-Amino-4-(3-chlorobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A solution of 2-(3-chlorobenzoyl)-3-phenylaminoacrylonitrile (63 mg,0.22 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methylbenzamidetrifluoroacetate (72 mg, 0.22 mmol, 1 eq), and triethylamine (31 μL,0.22 mmol, 1.0 eq) in 10 mL of ethanol was heated to 65° C. for 20 h.After cooling, the mixture was concentrated and the residue purified byflash chromatography on silica gel packed and eluted with 7/3hexanes/ethyl acetate to remove byproducts followed by 3/2 ethylacetate/hexanes to elute the title compound (33 mg, 38%) as a brownsolid. HPLC (4 minute 10-95 gradient) t_(R) 2.35 min; MS m/z 395.1[M+H]⁺; ¹H NMR (CD₃OD), δ 7.92 (d, J=7.2 Hz, 1H), 7.77 (m, 4H), 7.55 (m,3H), 2.85 (m, 1H), 2.23 (s, 3H), 0.80 (d, J=5.5 Hz, 2H), 0.63 (d, J=2.0Hz, 2H) ppm; ¹³C NMR (CD₃OD), δ 187.1, 168.1, 151.9, 141.0, 140.9,140.0, 134.9, 133.8, 132.8, 130.9, 130.5, 129.4128.1, 127.0, 126.1,125.6, 102.6, 22.1, 15.7, 4.6 ppm.

Example 42 Preparation of3-[5-Amino-4-(3-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

Similar procedure as Example 41 except that 3-methylbenzoylacetonitrilewas used in place of 3-chlorobenzoylacetonitrile. HPLC (4 minute 10-95gradient) t_(R) 2.27 min; MS m/z 375.16 [M+H]⁺; ¹H NMR (CD₃OD), δ 7.92(d, J=7.0 Hz, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.57 (m, 3H), 7.42 (m,2H), 2.85 (heptet, J=3.6 Hz, 1H), 2.45 (s, 3H), 2.23 (s, 3H), 0.80 (d,J=5.4 Hz, 2H), 0.64 (s, 2H) ppm.

Example 43 Preparation of3-[5-Amino-4-(2-methylbenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as Example 41 except that 2-methylbenzoylacetonitrilewas used in place of 3-chlorobenzoylacetonitrile. HPLC (4 minute 10-90gradient) t_(R) 2.21 min; MS m/z 375.15 [M+H]⁺.

Example 44 Preparation of3-[5-Amino-4-(2-methoxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as Example 41 except that 2-methoxybenzoylacetonitrilewas used in place of 3-chlorobenzoylacetonitrile. HPLC (4 minute 10-90gradient) t_(R) 2.03 min; MS m/z 391.16 [M+H]⁺.

Example 45 Preparation of3-[5-Amino-4-(4-chlorobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as Example 41 except that 3-methylbenzoylacetonitrilewas used in place of 3-chlorobenzoylacetonitrile. HPLC (4 minute 10-90gradient) t_(R) 1.65 min; MS m/z 394.2 [M+H]⁺.

Example 46 Preparation of3-[5-Amino-4-(2-chlorobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 2-(2-Chlorobenzoyl)-3-phenylaminoacrylonitrile

A solution of 2-chlorobenzoylacetonitrile (1.0 g, 5.6 mmol, 1.0 eq) anddiphenylformamidine (1.10 g, 5.6 mmol, 1.0 eq) in 50 mL of toluene washeated to 85° C. overnight. The heat source was removed and desiredproduct slowly began to precipitate from solution. The resulting solidwas filtered and dried to provide the desired product (826 mg, 52%).HPLC (4 minute 10-90 gradient) t_(R) 3.13 min; MS m/z 283.2 [M+H]⁺.

B.3-[5-Amino-4-(2-chlorobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A solution of 2-(2-chlorobenzoyl)-3-phenylaminoacrylonitrile (93 mg,0.33 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methylbenzamidetrifluoroacetate (104 mg, 0.33 mmol, 1 eq), and triethylamine (31 μL,0.22 mmol, 1.0 eq) in 20 mL of ethanol was heated to 60° C. for 48 h.After cooling, the mixture was concentrated and the residue wasdissolved in minimal ethyl acetate. 100 ml diethyl ether was added andthe precipitate was filtered and dried to provide desired product (50mg, 39%). HPLC (4 minute 10-90 gradient) t_(R) 2.51 min; MS m/z 395.1[M+H]⁺; ¹H NMR (DMSO), δ 8.50 (d, J=3.8 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H),7.84 (s, 1H), 7.57 (m, 5H) 7.32 (s, 1H), 7.01 (s, 2H) 3.37 (m, 2H), 2.86(m, 1H), 2.14 (s, 3H), 1.09 (t, 2H), 0.68 (m, 2H), 0.58 (m, 2H) ppm

Example 47 Preparation of3-[5-Amino-4-(3-methoxy-benzoyl)-pyrazol-1-yl]-4,N-dimethyl-benzamide

A. 3-methxoybenzoylacetonitrile

To a stirred solution of ethyl 3-methoxybenozoate (3.05 mL, 18.6mmol, 1. eq) and acetonitrile (1.19 mL, 22.9 mmol, 1.23 eq) in 5 mL ofTHF at −50° C. under N₂ was added via cannula a freshly preparedsolution of LDA (diisopropylamine, 5.3 mL, 38.0 mmol, 2.04 eq and 2.5 Mn-butyllithium in hexanes, 15.25 mL, 38.0 mmol, 2.04 eq). The reactionwas stirred at this temperature for 3 h then warmed to 0° C. for 1 h.The reaction was quenched with 10 mL of sat. NH₄Cl and allowed to warmto room temperature. The mixture was extracted with EtOAc and theorganic layer washed with water and brine, dried (Na₂SO₄), andconcentrated. The residue was purified by flash chromatography on silicagel to provide the product as an off-white solid.

B. 2-(3-Methoxybenzoyl)-3-phenylamino-acrylonitrile

A solution of 3-methoxybenzoylacetonitrile (1.20 g, 68.5 mmol, 1.0 eq)and diphenylformamidine (1.34 g, 68.5 mmol, 1.0 eq) in 25 mL of toluenewas stirred at room temperature for 2 h then heated to 100° C.overnight. The solution was cooled and diluted with hexanes. Theresulting solid was filtered and dried to provide the desired product.HPLC (4 minute 10-90 gradient) t_(R) 3.05 min; MS m/z 279.2 [M+H]⁺.

C. 3-[5-Amino-4-(3-methoxybenzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid

A solution of 2-(3-chlorobenzoyl)-3-phenylaminoacrylonitrile (63 mg,0.22 mmol, 1.0 eq), 3-hydrazino-4-methylbenzoic acid hydrochloride (72mg, 0.22 mmol, 1 eq), and triethylamine (31 μL, 0.22 mmol, 1.0 eq) in 10mL of ethanol was heated to 65° C. for 20 h. After cooling, the mixturewas concentrated and the residue purified by flash chromatography onsilica gel packed and eluted with 7/3 hexanes/ethyl acetate to removebyproducts followed by 3/2 ethyl acetate/hexanes to elute the titlecompound (15 mg, 32%) as a brown solid. HPLC (4 minute 10-90 gradient)t_(R) 2.13.min; MS m/z 352.2 [M+H]⁺.

D. 3-[5-Amino-4-(3-methoxybenzoyl)-pyrazol-1-yl]-4,N-dimethyl-benzamide

To a stirred solution of3-[5-Amino-4-(3-methoxybenzoyl)-pyrazol-1-yl]-4-methylbenzoic acid C (50mg, 0.14 mmol, 1.0 eq) in 10 mL of DMF was added EDCI (41 mg 0.21 mmol,1.5 eq), HOBt (29 mg, 1.5 mmol, 2.0 eq), and diisopropylethylamine (55mg, 0.43 mmol, 3.0 eq) and the solution was stirred for 15 minutes atroom temperature when methylamine hydrochloride (13 mg, 0.19 mmol, 1.5eq) was added and the reaction stirred for 1 hour. The mixture wasdiluted with EtOAc (300 mL) and washed with water (2×25 mL) and brine(25 mL), dried (Na₂SO₄) and concentrated. The product was purified byflash chromatography on silica gel to provide the product to provide theproduct (15 mg, 32%) as a brown solid: HPLC (4 minute 10-90 gradient)t_(R) 1.97 min; MS m/z 365.2 [M+H]⁺.

Example 48 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid ethyl ester

A. 5-Amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acidethyl ester

To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride(Example 3A, 478 mg, 2.36 mmol, 1.0 eq) in 20 mL of ethanol were addedethyl(ethoxymethylene)cyanoacrylate (399 mg, 2.36 mmol, 1.0 eq) andtriethylamine (329 μL, 2.36 mmol, 1.0 eq) and the mixture was heated at65° C. for 5 hrs. After standing at room temperature overnight,additional 3-hydrazino-4-methylbenzoic acid hydrochloride (159 mg, 0.78mmol, 0.3 eq) and triethylamine (110 μL, 0.78 mmol, 0.3 eq) and heatedfor 2.5. The mixture was cooled to room temperature and concentrated.The crude residue was purified by flash chromatography on silica gel(gradient elution from 7/3 hexanes/EtOAc to 1/1 to elute byproductsfollowed by EtOAc and 9/1 EtOAc/MeOH to elute product) to provide theproduct as a brown solid (464 mg, 68%). HPLC (4 minute 10-95 gradient)t_(R) 1.87 min; MS m/z 290.1 [M+H]⁺; ¹H NMR (CD₃OD), δ 8.08 (d, J=7.0Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 4.29 (q,J=7.1 Hz, 2H), 2.19 (s, 3H), 1.35 (d, J=7.1 Hz, 3H), ppm; ¹³C NMR(CD₃OD), δ 166.5, 163.8, 150.4, 141.7, 139.9, 135.3, 130.8, 129.5,128.6, 93.8, 58.8, 15.8, 12.9 ppm.

B.5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid ethyl ester

To a solution of5-amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acidethyl ester (47 mg, 0.16 mind, 1.0 eq), EDCI (62 mg, 0.32 mmol, 2.0 eq),HOBt (44 mg, 0.32 mmol, 2.0 eq), and diisopropylethyl amine (119 μL,0.32 mmol, 2.0 eq) in DMF (5 mL) which had been stirred at RT for 15 minwas added cyclopropylamine (23 μL, 0.32 mmol, 2.0 eq). After stirringovernight, the solution was diluted with EtOAc and water and the organiclayer was washed with water and brine, dried (Na₂SO₄) and concentrated.The crude residue was purified by flash chromatography on silica geleluted with 8/2 EtOAc/hexanes to provide the product as a colorless oil(42 mg, 79%). HPLC (4 minute 10-95 gradient) t_(R) 1.84 min; MS m/z329.09 [M+H]⁺; ¹H NMR (CD₃OD), δ 7.96 (s, 1H, NH), 7.88 (d, J=7.9 Hz,1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.28 (q, J=7.1Hz, 2H), 2.83 (m, 1H), 2.16 (s, 3H), 1.35 (d, J=7.0 Hz, 3H), 0.78 (dd,J=12.3, 7.0 Hz, 2H), 0.63 (dd, J=7.0, 4.5 Hz, 2H) ppm; ¹³C NMR (CD₃OD),δ 170.1, 165.8, 152.3, 142.1, 141.8, 137.2, 134.6, 132.8, 130.0, 128.2,128.1, 95.8, 60.8, 24.1, 17.6, 14.9, 6.6 ppm.

Example 49 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methyl-1H-pyrazole-4-carboxylicacid ethyl ester

A.5-Amino-1-(5-carboxy-2-methyl-phenyl)-3-methyl-1H-pyrazole-4-carboxylicacid ethyl ester

To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride(Example 3A, 353 mg, 1.74 mmol, 1.0 eq) in 15 mL of ethanol were added2-cyano-3-ethoxy-but-2-enoic acid ethyl ester (prepared as described byXia et al., J. Med. Chem., 1997, 40, 4372) (319 mg, 1.746 mmol, 1.0 eq)and triethylamine (242 μL, 1.74 mmol, 1.0 eq) and the mixture was heatedat 65° C. overnight. The mixture was cooled to room temperature andconcentrated. The crude residue was purified by flash chromatography onsilica gel (loaded with CH₂Cl₂, and packed and eluted with gradient from6/4 hexanes/EtOAc to elute byproducts followed by 8/2 EtOAc/hexanes and8/2 EtOAc/MeOH to elute product) to provide the product as a brown solid(464 mg, 68%). HPLC (4 minute 10-95 gradient) t_(R) 1.97 min; MS m/z304.1 [M+H]⁺

B.5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methyl-1H-pyrazole-4-carboxylicacid ethyl ester

To a solution of5-amino-1-(5-carboxy-2-methyl-phenyl)-3-methyl-1H-pyrazole-4-carboxylicacid ethyl ester (150 mg, 0.49 mmol, 1.0 eq), EDCI (190 mg, 0.98 mmol,2.0 eq), HOBt (134 mg, 0.98 mmol, 2.0 eq), and diisopropylethyl amine(362 μL, 0.98 mmol, 2.0 eq) in DMF (5 mL) which had been stirred at RTfor 15 min was added cyclopropylamine (68 μL, 0.98 mmol, 2.0 eq). Afterstirring overnight, the solution was diluted with EtOAc and water andthe organic layer was washed with water (2×) and brine, dried (Na₂SO₄)and concentrated. The crude residue was purified by flash chromatographyon silica gel (gradient elution, 3/2 EtOAc/hexanes then 100% EtOAc) toprovide the product as a white solid (29 mg, 17%). HPLC (4 minute 10-95gradient) t_(R) 1.97 min; MS m/z 343 [M+H]⁺; ¹H NMR (CD₃OD), δ 7.87 (d,J=7.1 Hz, 1H), 7.76 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 4.29 (q, J=7.0 Hz,2H), 2.84 (m, 1H), 2.34 (s, 3H), 2.18 (s, 3H), 1.36 (t, J=7.0 Hz, 3H),0.79 (d, J=5.5 Hz, 2H), 0.62 (s, 2H) ppm; ¹³C NMR (CD₃OD), δ 168.1,164.4, 151.3, 149.8, 140.1, 135.2, 132.6, 130.7, 127.9, 126.3, 92.0,58.6, 22.1, 15.7, 12.9, 12.6, 4.6 ppm.

Example 50 Preparation of5-Amino-3-[(3-chloro-benzylcarbamoyl)-methoxy]-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid ethyl ester

A.5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-(2-hydroxy-ethoxy)-1H-pyrazole-4-carboxylicacid ethyl ester

A stirred solution of cyano-[1,3]dioxolan-2-ylidene-acetic acid ethylester (prepared as described by Neidlein and Kikelj, Synthesis, 1988,981, 266 mg, 1.45 mmol, 1.0 eq),N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (Example6C, 463 mg, 1.45 mmol, 1.0 eq), and triethylamine (405 μL, 2.9 mmol, 2.0eq) in 20 mL of ethanol was heated to 65° C. overnight. After cooling toroom temperature, the mixture was concentrated and the residue purifiedby flash chromatography on silica gel (eluted with 1/1 hexanes/EtOAcfollowed by 100% EtOAc) to provide the desired compound as a tan solid(350 mg, 62%). HPLC (4 minute 10-95 gradient) t_(R) 1.59 min; MS ink389.06 [M+H]⁺; ¹H NMR (CD₃OD), δ 7.87 (d, J=7.9 Hz, 1H), 7.78 (s, 1H),7.49 (d, J=7.8 Hz, 1H), 4.29 (dd, J=14.9, 6.9 Hz, 2H), 4.19 (d, J=4.3Hz, 2H), 3.84 (d, J=4.4 Hz, 2H), 2.84 (m, 1H), 2.22 (s, 3H), 1.35 (t,J=7.3 Hz, 3H), 0.81 (d, J=5.3 Hz, 2H), 0.63 (s, 2H) ppm.

B.5-Amino-3-carboxymethoxy-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid ethyl ester

To a stirred solution of alcohol 50A (48 mg, 0.12 mmol, 1.0 eq) in 5 mLof acetonitrile was added 2,2′,6,6′-tetramethylpiperidinyloxyl (TEMPO)(catalytic) and the solution heated to 35° C. Then a solution of sodiumchlorite (17 mg, 0.24 mmol, 2.0 eq) in 2 mL of water (2 mL) and anaqueous solution of sodium hypochlorite diluted to 2% (1 mL) were addedsimultaneously dropwise and the heating was continued for 24 hours. Abright orange color developed. The reaction was cooled to RT and dilutedwith water then quenched with 1M Na₂SO₃ and stirred for 30 minutes. Themixture was washed with EtOAc, then the pH of the aqueous layer wasadjusted from pH=8 to pH=2 with 3 M HCl, and extracted with CH₂Cl₂. TheCH₂Cl₂ extracts were dried and concentrated to provide the product as ayellow solid. HPLC (4 minute 10-95 gradient) t_(R) 1.70 min; MS m/z403.02 [M+H]⁺; ¹H NMR (CD₃OD), δ 7.83 (d, J=7.9 Hz, 1H), 7.52 (s, 1H),7.46 (d, J=7.9 Hz, 1H), 4.73, (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 2.84 (m,1H), 2.18 (s, 3H), 1.31 (t, J=7.0 Hz, 3H), 0.78 (d, J=6.1 Hz, 2H), 0.62(s, 2H) ppm; ¹³C NMR (CD₃OD), δ 171.1, 170.2, 168.4, 163.6, 159.7,151.3, 140.5, 135.2, 132.5, 130.7, 127.6, 126.2, 80.9, 59.6, 58.7, 22.1,15.8, 12.5, 4.6 ppm.

C.5-Amino-3-[(3-chloro-benzylcarbamoyl)-methoxy]-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid ethyl ester

To a stirred solution of acid 50B (28 mg, 0.7 mmol, 1.0 eq), EDCI (32mg, 0.17 mmol, 2.4 eq), HOBt (22 mg, 0.16 mmol, 2.4 mmol) in 3.0 mL ofDMF at room temperature was added 3-chlorobenzylamine (18 μL, 0.07 mmol,1.0 eq) and the mixture was stirred overnight. The mixture was dilutedwith EtOAc, washed with water (×2) and brine, dried (Na₂SO₄), andconcentrated. The residue was purified by flash chromatography on silicagel eluted with 9/1 EtOAc/hexanes to provide the product as a clear oil(16 mg, 44%). HPLC (4 minute 10-95 gradient) t_(R) 2.34 min; MS m/z525.99 [M+H]⁺; ¹H NMR (CD₃OD), δ 7.85 (d, J=7.9 Hz, 1H), 7.56 (s, 1H),7.47 (d, J=8.0 Hz, 1H), 7.25 (m, 3H), 4.73, (s, 2H), 4.45 (s, 2H), 4.25(q, J=7.0 Hz, 2H), 2.84 (m, 1H), 2.17 (s, 3H), 1.27 (t, J=7.0 Hz, 3H),0.80 (dd, J=12.3, 6.7 Hz, 2H), 0.62 (d, J=2.2 Hz, 2H) ppm; ¹³C NMR(CD₃OD), δ 168.9, 168.3, 163.4, 159.6, 151.1, 140.3, 140.1, 135.2,133.6, 132.6, 130.8, 129.1, 127.7, 126.6, 126.4, 125.0, 66.3, 58.8,41.1, 22.1, 15.9, 12.9, 4.6 ppm.

Example 51 Preparation of3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

A. 3-Hydrazino-4-methylbenzoic acid hydrochloride

A solution of 3-amino-4-methyl benzoic acid 1 (100 g, 0.66 mol, 1.0equiv) in water (1.78 L) was cooled to 0-5° C. using ice-water. Conc.HCl (1.78 L) and sodium nitrite (68.5 g, 0.99 mol, 1.5 equiv) were addedin sequence at 0-5° C. The reaction mixture was stirred at the 0-5° C.for 1 hour. Stannous chloride dihydrate (336 g, 1.488 mol, 2.25 equiv)in conc. HCl (540 ml) was added at 0-5° C. The mixture was stirred atthe same temperature for 2 hours. Solid formed during the course of thereaction was filtered and washed with water (3×500 ml). Dried undervacuum at 25-30° C. for 15 hours to provide then the crude material was(110 g) dissolved in ethanol (1 L) and stirred at 70° C. for 1 hour. Thematerial is filtered at hot and washed with ethanol (50 ml) and airdried to get the pure hydrazine 2 (60 g, 45%) as an off white solid.

B. 3-(5-Amino-4-benzoyl-pyrazol-1-yl)-4-methylbenzoic acid

To a stirred solution of hydrazine 2 (59 g, 0.29 mol, 1.0 equiv) inethanol (4.5 L) was added 3 (65 g, 0.262 mol, 0.9 equiv, preparation:Grothasu, Davis, J. Am. Chem. Soc., 58, 1334 (1936)) and triethylamine(29 g, 0.29 mol, 1.0 equiv). The mixture was heated to 65° C. At 65° C.the reaction mixture became homogenous and was stirred at 65° C. for 4hours. Product was precipitated out during the reaction. The solids werefiltered in hot condition and dried to provide acid 4 (45 g, 53%) as anoff-white crystalline solid. HPLC (Waters X-Terra 5 micron C18 column4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H₂O/acetonitrile40/60, 30 min elution) t_(R) 2.12 min, 96.6% purity; ¹H NMR (DMSO-d₆,400 MHz) is consistent with Example 3.

C. 3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamide

To a stirred solution of acid 4 (46 g, 0.143 mol, 1.0 equiv) in DMF (1.9L) was added EDCI (57.5 g, 0.299 mol, 2.09 equiv), HOBt (41.4 g, 0.306,2.14 equiv) and diisopropylethylamine (76.6 g, 0.59 mol, 4.15 equiv) andthe solution was stirred for 20 minutes at room temperature. Then it wascooled to 15-20° C. and cyclopropylamine (20.6 g, 0.36 mol, 2.51 equiv)was added and stirred at room temperature. The reaction was monitored byTLC. After 14 hours, since the reaction was not complete and additionalcyclopropylamine (9.36 g, 0.16 mol, 1.14 equiv) was added and stirringwas continued for two hours. DMF was removed under reduced pressure at50-55° C. To the residue EtOAc (1 L) and water (500 ml) were added andthe mixture was stirred for 10 minutes. The mixture was extracted andthe organic layer was collected. The aqueous layer was extracted withEtOAc (2×250 ml). The combined organic layer was washed with sodiumbicarbonate (2×500 ml) and brine (2×500 ml), dried over anhydrous sodiumsulfate and concentrated. To the residue EtOAc/dichloromethane/hexane(50 ml/50 ml/50 ml) was added, the mixture was stirred for 10 minutes,and filtered to provide the product (34.1 g, 65.7%) as an off whitecrystalline solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250mm, 1.0 mL/min, mobile phase: 0.1% TEA in H₂O/acetonitrile 50/50, 30 minelution) t_(R) 5.53 min, 99.3% purity; MS m/z 360 [M]⁺; ¹H NMR (DMSO-d₆,400 MHz) is consistent with Example 4.

Example 52 Preparation of3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of3-[5-amino-4-(3-iodobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide(110 mg, 0.23 mmol) in DMF (5 mL) was added CuCN (40 mg, 0.45 mmol) andtetrakis(triphenylphosphine)palladium (catalytic) and the mixture washeated at 100° C. over night under N₂. The solvent was removed and theresidue was suspended in EtOAc, and solids were filtered off. Thefiltrate was washed by water, brine, dried over Na₂SO₄ and concentrated.The crude product was purified by column chromatography on silica gel(EtOAc). Product was obtained as a beige solid (30 mg, 34%). HPLC (4minute 10-90 gradient) t_(R) 2.02 min; MS m/z 386.13 [M+H]⁺.

Example 53 Preparation of3-[5-Amino-4-(3-[1,3,4]oxadiazol-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A.3-[5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carbonyl]-benzoicacid

To a stirred solution of3-[5-amino-4-(3-formylbenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide(900 mg) in CH₃CN (25 mL) were added NaH₂PO₄ (55 mg in 2 mL water) andH₂O₂ (1.3 g, 30% solution in water) followed by the dropwise addition ofan aqueous solution of NaClO₂ (365 mg) at 10° C. The mixture was stirredat this temperature for 4 h before Na₂SO₃ was added. Solvent was removedand residue was dissolved in EtOAc, the organic layer was washed withwater and brine and concentrated. The crude product was purified bycolumn chromatography on silica gel eluted with EtOAc followed byEtOAC:AcOH=100:1), to provide the desired intermediate as a beige foam(345 mg, 37%).

B.3-[5-Amino-4-(3-hydrazinocarbonylbenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

Compound 53A (50 mg, 0.12 mmol), t-butyl carbazate (33 mg, 0.24 mmol),EDCI (46 mg, 0.24 mmol) and HOBt (37 mg, 0.24 mmol) were dissolved inDMF (5 mL, dry) and stirred at room temperature over night. Solvent wasremoved, the residue was dissolved in EtOAc and the organics were washedby water, K₂CO₃ aqueous solution, brine, and dried over Na₂SO₄. ThenTFA/DCE (5 mL, 1:1) was added and stirred at room temperature for 30min. Solvent was removed, the residue was dissolved in EtOAc, washedwith K₂CO₃ aqueous solution and dried over Na₂SO₄. Solvent was removedto provide compound B as a beige solid (45 mg, 88%).

C.3-[5-Amino-4-(3-[1,3,4]oxadiazol-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

Trimethyl orthoformate (2 mL) was added to the solution of compound 53Bin MeOH (2 mL) and stirred at room temperature over night. Solvent wasremoved, solid residue was dissolved in 1,4-dioxane, and five drops of a4M solution of HCl in dioxane was added and the mixture was heated inthe microwave at 120° C. for 30 min. The solvent was removed, theresidue was dissolved in EtOAc, and the organics were washed with water,brine and the crude product was purified by preparative TLC(EtOAc:MeOH=95:5) to provide product as a beige solid (25 mg, 63%). HPLC(4 minute 10-90 gradient) t_(R) 1.81 min; MS m/z 429.13 [M+H]⁺.

Example 54 Preparation of3-{5-Amino-4-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 53 except trimethylorthoacetate was usedin place of trimethyl orthoformate. HPLC (4 minute 10-90 gradient) t_(R)1.84 min; MS m/z 443.15 [M+H]⁺.

Example 55 Preparation of3-{5-Amino-4-[3-(pyrrolidine-1-carbonyl)-benzoyl]-imidazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except pyrrolidine was used in placeof isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.93 min; MS m/z458.2 [M+H]⁺.

Example 56 Preparation of3-[5-Amino-4-(3-cyclopropylcarbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except cyclopropylamine was used inplace of isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.74 min;MS m/z 444.14 [M+H]⁺.

Example 57 Preparation of3-[5-Amino-4-(3-carbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 21 except ammonia was used in place ofisopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 1.51 min; MS m/z404.2 [M+H].

Example 58 Preparation of3-[5-Amino-4-(3-isopropylcarbamoylbenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

Similar procedure as in Example 21B except3-[5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carbonyl]-benzoicacid was used in place of3-[5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-imidazole-4-carbonyl]-benzoicacid. HPLC (4 minute 10-90 gradient) t_(R) 1.89 min; MS m/z 446.2[M+H]⁺.

Examples 59-69

The following examples were prepared with a procedure similar to Example58 except the appropriate amine was used in place of isoprpylamine.

TABLE 1 HPLC MS m/z Ex Structure Name t_(R)(min) [M + H]⁺ 59

3-[5-Amino-4-(4- methylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 1.03 418.2 60

3-[5-Amino-4-(4- cyclopropylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 1.77 444.26 61

3-[5-Amino-4-(3- carbamoyl-benzoyl)- pyrazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 1.64 404.16 62

3-{5-Amino-4-[3- (piperazine-1- carbonyl)-benzoyl]- pyrazol-1-yl}-N-cyclopropyl-4-methyl- benzamide 2.27 473.21 63

3-[5-Amino-4-(3- dimethylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 1.71 432.21 64

3-{5-Amino-4-[3- (cyclopropylmethyl- carbamoyl)-benzoyl]-pyrazol-1-yl}-N- cyclopropyl-4-methyl- benzamide 1.9 458.25 65

3-[5-Amino-4-(3- ethylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 1.77 432.18 66

3-[5-Amino-4-(3- methylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 1.69 418.17 67

3-[5-Amino-4-(3- cyclopentylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 2.0 472.23 68

3-[5-Amino-4-(3- isopropylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 1.89 446.2 69

3-[5-Amino-4-(3- cyclopropylcarbamoyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 1.82 444.15

Examples 70-75

The following examples were prepared with a procedure similar to Example11 except the appropriate amine was used in place of 1-methylpiperazine.

TABLE 2 HPLC MS m/z Ex Structure Name t_(R)(min) [M + H]⁺ 70

3-(5-Amino-4-{3-[(3- chloro-benzylamino)- methyl]-benzoyl}-pyrazol-1-yl)-N- cyclopropyl-4-methyl- benzamide 1.74 514.17 71

3-[5-Amino-4-(3-{[2- (3-chloro-phenyl)- ethylamino]-methyl}benzoyl)-pyrazol-1- yl]-N-cyclopropyl-4- methyl-benzamide 1.74 528.2 72

3-(5-Amino-4-{3-[4-(3- chloro-phenyl)- piperazin-1-ylmethyl]-benzoyl}-pyrazol-1- yl)-N-cyclopropyl-4- methyl-benzamide 1.82 569.23 73

3-[5-Amino-4-(3-{[2- (2-benzyloxy-5- chloro-phenyl)-ethylamino]-methyl}- benzoyl)-pyrazol-1- yl]-N-cyclopropyl-4-methyl-benzamide 2.11 634.2 74

3-(5-Amino-4-{3-[(2- morpholin-4-yl- ethylamino)-methyl]-benzoyl}-pyrazol-1- yl)-N-cyclopropyl-4- methyl-benzamide 1.03 503.22 75

3-(5-Amino-4-{3-[(3- morpholin-4-yl- propylamino)-methyl]-benzoyl}-pyrazol-1- yl)-N-cyclopropyl-4- methyl-benzamide 1.02 517.25

Examples 76-93

The following examples were prepared with a procedure similar to Example17 except the appropriate grignard reagent was used in place ofphenylmagnesium bromide.

TABLE 3 HPLC MS m/z Ex Structure Name t_(R)(min) [M + H]⁺ 76

3-[5-Amino-4- (pyridine-2-carbonyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 1.56 362.23 77

3-[5-Amino-4-(2- methyl-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 1.95 375.1 78

3-[5-Amino-4-(3,4- difluoro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.53 397.17 79

3-[5-Amino-4-(3- fluoro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.23 379.2 80

3-[5-Amino-4-(3,4- dichloro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.95 429.11 81

3-[5-Amino-4-(3- methoxy-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.22 391.19 82

3-[5-Amino-4-(4- fluoro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.29 379.1 83

3-[5-Amino-4-(3,5- dichloro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 3.07 429.13 84

3-[5-Amino-4-(4- methoxy-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.12 391.11 85

3-[5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)-1H-imidazole-4-carbonyl]- benzoic acid tert-butyl ester 2.53 461.05 86

3-[5-Amino-4-(3,5- difluoro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.58 397.18 87

3-[5-Amino-4- (benzo[1,3]dioxole-5- carbonyl)-imidazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 2.12 405.11 88

3-[5-Amino-4-(4- chloro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.54 395.15 89

3-[5-Amino-4-(3,4- dimethoxy-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 1.95 420.1 90

3-[5-Amino-4-(3- benzyloxy-benzoyl) imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.51 467 91

3-[5-Amino-4-(4- fluoro-3-methyl- benzoyl)-imidazol-1-yl]-N-cyclopropyl-4- methylbenzamide 2.25 393 92

{3-[5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)-1H-imidazole-4-carbonyl]- phenoxy}-acetic acid tert-butyl ester 2.23 491 93

3-[5-Amino-4-(3- chloro-benzoyl)- imidazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.54 395.17

Example 94 Preparation of3-(5-Amino-4-benzoyl-2-methyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in except 17 except triethylorthoacetate was usedin place of triethylorthoformate. HPLC (4 minute 10-90 gradient) t_(R)1.56 min; MS m/z 375 [M+H]⁺.

Example 95

Preparation of3-(5-Amino-4-benzoyl-2-propyl-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in except 17 except triethylorthbutyrate was usedin place of triethylorthoformate. HPLC (4 minute 10-90 gradient) t_(R)2.14 min; MS m/z 403 [M+H]⁺.

Example 96 Preparation of3-[5-Amino-4-(3-carbamoylmethoxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A.{3-[5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carbonyl]-phenoxy}-aceticacid

To a stirred solution of3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide(400 mg, 1.06 mmol) and t-butyl chloroacetate (319 mg, 2.12 mmol) in DMF(20 mL) was added K₂CO₃ (292 mg, 2.12 mmol) and the mixture was heatedat 100° C. overnight. The solvent was removed, and the residue wassuspended in EtOAc, washed by water, brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by column chromatography onsilica gel (EtOAc:Hexane=3:1) to provide the product as a light yellowoil (140 mg, 27%).

B.{3-[5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carbonyl]-phenoxy}-aceticacid

The oil (180 mg, 0.37 mmol) from last step was dissolved in DCM (5 mL),TFA (5 mL) was added and stirred at room temperature over night.Volatile organics were removed, toluene was added then removed in vacuoto provide the product as a white solid (140 mg, 88%).

C.3-[5-Amino-4-(3-carbamoylmethoxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of the intermediate obtained in the previous step in THF(5 mL) was added SOCl₂ (1 mL) and the mixture was stirred at roomtemperature for 2 h. The volatiles were removed, then NH₃ (0.5 M dioxanesolution) was added and the mixture was stirred at room temperature for30 min. The solvent was removed, and the residue was purified bypreparative TLC (EtOAc:MeOH:Et₃N=100:10:1) and then by preparatory HPLCto provide the product as a beige solid (4.2 mg, 10%). HPLC (4 minute10-90 gradient) t_(R) 1.78 min; MS m/z 434.14 [M+H].

Examples 97-105

The following examples were prepared with a procedure similar to Example96 except the appropriate amine was used in place of ammonia.

TABLE 4 HPLC MS m/z Ex Structure Name t_(R)(min) [M + H]⁺  97

3-(5-Amino-4-{3-[2- (4-methyl- piperazin-1-yl)-2- oxo-ethoxy]-benzoyl}-pyrazol-1- yl)-N-cyclopropyl-4- methyl-benzamide 1.56 517.22 98

3-{5-Amino-4-[3-(2- oxo-2-piperazin-1- yl-ethoxy)-benzoyl]-pyrazol-1-yl}-N- cyclopropyl-4- methyl-benzamide 1.48 503.21  99

3-(5-Amino-4-{3-[2- (3-amino-pyrrolidin- 1-yl)-2-oxo-ethoxy]-benzoyl}-pyrazol-1- yl)-N-cyclopropyl-4- methyl-benzamide 1.63 503.2 100

3-(5-Amino-4-{3-[2- (3-methylamino- pyrrolidin-1-yl)-2- oxo-ethoxy]-benzoyl}-pyrazol-1- yl)-N-cyclopropyl-4- methyl-benzamide 1.51 517.22101

3-(5-Amino-4-{3-[2- (3,5-dimethyl- piperazin-1-yl)-2- oxo-ethoxy]-benzoyl}-pyrazol-1- yl)-N-cyclopropyl-4- methyl-benzamide 1.62 531.26102

3-{5-Amino-4-[3-(2- morpholin-4-yl-2- oxo-ethoxy)- benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4- methyl-benzamide 1.92 504.2 103

3-[5-Amino-4-(3- {[(1H- benzoimidazol-2- ylmethyl)- carbamoyl]-methoxy)-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4- methyl-benzamide 1.54564.21 104

3-[5-Amino-4-(3- {[2-(2-benzyloxy-5- chloro-phenyl)- ethylcarbamoyl]-methoxy}-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4- methyl-benzamide 3.2678.26 105

3-[5-Amino-4-(3- {[2-(5-chloro-2- hydroxy-phenyl)- ethylcarbamoyl]-methoxy}-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4- methyl-benzamide 2.49588.19

Example 106 Preparation of3-[5-Amino-4-(3-pyrazin-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

To a stirred solution of3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide(130 mg, 0.27 mmol) and 2-tributylstannylpyrazine (119 mg, 0.32 mmol) inDMF (2 mL) was added tetrakis(triphenylphosphine) palladium (catalytic)and the mixture was heated in microwave at 160° C. for 15 min. Thesolvent was removed and the residue was dissolved in EtOAc. The organicswere washed by water, brine and concentrated. The crude material waspurified by preparatory HPLC to provide the desired product as beigesolid (6.2 mg, 5%). HPLC (4 minute 10-90 gradient) t_(R) 2.12 min; MSm/z 439.19 [M+H]⁺.

Example 107 Preparation of3-[5-Amino-4-(3-pyridin-2-yl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

Similar procedure as in Example 106 except 2-tributylstannylpyridine wasused in place of 2-tributylstannylpyrazine. HPLC (4 minute 10-90gradient) t_(R) 1.94 min; MS m/z 438.26 [M+H]⁺.

Example 108 Preparation of3-[5-Amino-4-(pyridine-2-carbonyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

A. 3-(5-Amino-4-cyano-pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamide

DIPEA (3.4 g, 26.5 mmol) was added to the solution ofN-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetate (8.45 g,26.5 mmol) and 2-ethoxymethylene malononitrile (3.2 g, 26.5 mmol) inEtOH (100 mL) and stirred at 65° C. for 3 h. The solvent was removed theresidue was suspended in EtOAc (−100 mL), and water was added to thissuspension. The solid product was filtered. The filtrate was washed bywater, brine, dried over Na₂SO₄, concentrated, and purified by columnchromatography on silica gel eluted with EtOAc. The product, combinedfrom filtration and chromatography, was obtained as a beige solid (7.1g, 96%).

B.3-[5-Amino-4-(pyridine-2-carbonyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Cyclohexylmagnesium chloride (5 mL, 2.0 M in Et₂O) was added dropwise tothe solution of 2-iodopyridine (1.03 g, 5 mmol) in THF (15 mL) at −20°C. The mixture was stirred at this temperature for 20 min before3-(5-Amino-4-cyano-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (140mg, 0.5 mmol) was added, then stirred at room temperature over night.The reaction was quenched by the addition of K₂CO₃ aqueous solution,then the mixture was extracted with EtOAc and the organic layers washedwith water and brine. Purification by column chromatography on silicagel eluted with EtOAc provided the product as a white solid (60 mg,33%). HPLC (4 minute 10-90 gradient) t_(R) 2.09 min; MS m/z 362.20[M+H]⁺.

Example 109 Preparation of3-(5-Amino-4-cyclopentanecarbonyl-pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamide

Similar procedure as in Example 17B except3-[5-amino-4-(3-cyano-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamidewas used in place of3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide andcyclopentylmagnesium bromide was used in place of phenyl magnesiumbromide. HPLC (4 minute 10-90 gradient) t_(R) 2.54 min; MS m/z 353.19[M+H]⁺.

Examples 110-126

The following examples were prepared with a procedure similar to Example109 except the appropriate grignard reagent was used in place ofcyclopentylmagnesium bromide.

TABLE 5 HPLC MS m/z Ex Structure Name t_(R)(min) [M + H]⁺ 110

3-[5-Amino-4- (benzo[1,3]dioxole-5- carbonyl)-pyrazol-1-yl]-N-cyclopropyl-4- methylbenzamide 2.67 405.16 111

3-[5-Amino-4-(2- fluoro-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4-methyl-benzamide 2.05 379.13 112

3-[5-Amino-4-(3- ethoxy-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4-methyl-benzamide 2.58 405.17 113

3-[5-Amino-4-(3- methoxy-benzoyl)- pyrazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.37 391.17 114

3-[5-Amino-4-(3- cyclopropoxy- benzoyl)-pyrazol-1- yl]-N-cyclopropyl-4-methyl-benzamide 2.68 417.2 115

3-[5-Amino-4-(4- methoxy-benzoyl)- pyrazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.24 391.19 116

3-[5-Amino-4-(3,4- dimethoxy-benzoyl)- pyrazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.11 421.17 117

3-[5-Amino-4-(4- methylsulfanyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 2.59 407.14 118

3-[5-Amino-4-(3- methylsulfanyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 2.61 407.15 119

3-[5-Amino-4-(4- fluoro-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4-methyl-benzamide 2.18 379.23 120

3-[5-Amino-4-(3- fluoro-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4-methyl-benzamide 2.18 379.15 121

3-[5-Amino-4-(3,4- difluoro-benzoyl)- pyrazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.25 3.97.16 122

3-[5-Amino-4-(3,5- difluoro-benzoyl)- pyrazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.28 397.17 123

3-[5-Amino-4-(4- fluoro-3-methyl- benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4- methyl-benzamide 2.32 393.23 124

3-[5-Amino-4-(4- fluoro-benzoyl)- pyrazol-1-yl]-N- cyclopropyl-4-methyl-benzamide 2.15 379.17 125

3-(5-Amino-4- cyclohexanecarbonyl- pyrazol-1-yl)-N-cyclopropyl-4-methyl- benzamide 2.75 367.22 126

3-[5-Amino-4-(3- vinyloxy-benzoyl)- pyrazol-1-yl]-N-cyclopropyl-4-methyl- benzamide 2.64 403.15

Example 127 Preparation of3-{5-Amino-4-[3-([1,3,4]oxadiazol-2-ylmethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methylbenzamide

A.3-[5-Amino-4-(3-hydrazinocarbonylmethoxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

Compound 97A (300 mg, 0.69 mmol), t-butyl carbazate (182 mg, 1.38 mmol),EDCI (263 mg, 1.38 mmol) and HOBt (211 mg, 1.38 mmol) were dissolved inDMF (10 mL, dry) and stirred at room temperature for 2 h. Solvent wasremoved, residue was dissolved in EtOAc, washed by water, K₂CO₃ aqueoussolution, brine, and dried over Na₂SO₄. Then TFA/DCE (5 mL, 1:1) wasadded and stirred at room temperature for 30 min. Solvent was removed,residue was dissolved in EtOAc, washed with K₂CO₃ aqueous solution anddried over Na₂SO₄. The crude residue was purified by columnchromatography on silica gel (EtOAc:MeOH=10:1), and the desired compoundwas obtained as a white solid (88 mg, 28%).

B.3-{5-Amino-4-[3-([1,3,4]oxadiazol-2-ylmethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methylbenzamide

Trimethyl orthoformate (3 mL) was added to the solution of compound 52B(48 mg, 0.11 mmol) in MeOH (3 mL) and stirred at room temperature overnight. Solvent was removed, solid residue was dissolved in 1,4-dioxane,five drops of HCl in dioxane (4M) was added, and the mixture heated inmicrowave at 120° C. for 30 min. Solvent was removed, residue wasdissolved in EtOAc, washed with water and brine. The crude product waspurified by preparatory HPLC, and the product was obtained as a whitesolid (3.3 mg, 6.7%). HPLC (4 minute 10-90 gradient) t_(R) 2.07 min; MSm/z 459.13 [M+H].

Example 128 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid (2-methyl-cyclohexyl)-amide

A.5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid

A solution of5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid ethyl ester (1.0 g, see Example 44), LiOH (1.2 g) in water/ethanol(15 ml/20 ml) was heated at 50° C. overnight. The solution wasneutralized with dilute HCl (2M), and extracted with ethyl acetate (200ml×2), dried over Na₂SO₄. The solvent was evaporated under reducedpressure and ethyl acetate and diethyl ether was added. The resultingsolid was filtered to give the desired5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylicacid. (0.8 g; yield: 88%).

B.5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid (2-methyl-cyclohexyl)-amide

A solution of5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylicacid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg) and HOBt (12mg) in DMF (0.75 ml) was reacted at room temperature for 24 h. Water (4ml) was added and the solution was extracted with ethyl acetate (3mL×2). The organic phase was then washed with water (3 mL), dried overNa₂SO₄ and evaporated. The residue was purified by preparative TLC plateto give the desired product5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylicacid (2-methylcyclohexyl)-amide (19 mg, 70%). HPLC (4 minute gradient)t_(R) 2.34 min; MS m/z 396.31 [M+H].

Examples 129-156

The following examples were prepared with a procedure similar to Example128 except the appropriate amine was used in place of2-methylcyclohexylamine.

TABLE 6 HPLC MS m/z Ex Structure Name t_(R)(min) [M + H]⁺ 129

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl- phenyl)-1H- pyrazole-4-carboxylic acid phenylamide 2.4 376.2 130

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl- phenyl)-1H- pyrazole-4-carboxylic acid (1- ethyl-propyl)-amide 2.16 370.3 131

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl- phenyl)-1H- pyrazole-4-carboxylic acid bicyclo[2.2.1]hept- 2-ylamide 2.41 394.3 132

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl- phenyl)-1H- pyrazole-4-carboxylic acid (1- ethy 2.57 406.2 133

3-[5-Amino-4-(2,5- dimethyl- pyrrolidine-1- carbonyl)-pyrazol-1-yl]-N-cyclopropyl- 4-methyl- benzamide 2.17 383.29 134

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl- phenyl)-1H- pyrazole-4-carboxylic acid 4- methoxy- benzylamide 2.15 420.3 135

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl- phenyl)-1H- pyrazole-4-carboxylic acid indan-1-ylamide 2.35 416.75 136

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid benzylamide 2.04 390.23 137

3-[5-Amino-4- (piperidine-1- carbonyl)-pyrazol-1- yl]-N-cyclopropyl-4-methyl-benzamide 2.05 368.16 138

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid cyclohexylamide 2.19 382.25 139

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid cyclopropylamide 1.72 340.23 140

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid 3- chlorobenzylamide 2.31 424.31 141

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid cyclopentylamide 2.03 368.29 142

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid 2,4- dichloro-benzylamide 2.54 458.24 143

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid cyclohexylmethyl- amide 2.38 396.4 144

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid 3,4- dichloro-benzylamide 2.5 458.23 145

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (4- methyl-cyclohexyl)- amide 2.45 396.32 146

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid 3- trifluoromethyl- benzylamide 2.44 458.25 147

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (4- tert-butyl- cyclohexyl)-amide 2.86 438.4 148

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (2,2- dimethyl-propyl)- amide 2.19 370.28 149

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid 3- methoxy- benzylamide 2.13 420.29 150

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid 4- fluoro-benzylamide 2.19 408.26 151

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (1- ethyl-pyrrolidin-2- ylmethyl)-amide 1.41 411.28 152

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid 2- methyl-benzylamide 2.26 404.33 153

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (pyridin-2-ylmethyl)- amide 1.39 391.14 154

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (2- morpholin-4-yl- ethyl)-amide 1.12 413.25 155

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (1- cyclohexyl-ethyl)- amide 2.53 410.45 156

5-Amino-1-(5- cyclopropylcarbamoyl- 2-methyl-phenyl)- 1H-pyrazole-4-carboxylic acid (1- phenyl-ethyl)-amide 2.22 404.28

Example 157 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid (2,2-dimethyl-propyl)-amide

Similar procedure as in Example 128 except neopentylamine was used inplace of isopropylamine. HPLC (4 minute 10-90 gradient) t_(R) 2.19 min;MS m/z 370.32 [M+H]⁺.

Example 158 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid (1-ethyl-pyrrolidin-2-ylmethyl)-amide

Similar procedure as in Example 128 except2-(aminomethyl)-1-ethylpyrrolidine was used in place of isopropylamine.HPLC (4 minute 10-90 gradient) t_(R) 1.41 min; MS m/z 411.25 [M+H]⁺.

Example 159 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

Similar procedure as in Example 128 except 1-(2-aminoethyl)pyrrolidinewas used in place of isopropylamine. HPLC (4 minute 10-90 gradient)t_(R) 1.34 min; MS m/z 397.22 [M+H]⁺.

Example 160 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylicacid cyclohexyl-methyl-amide

Similar procedure as in Example 57 except N-methylcyclohexylamine wasused in place of isopropylamine. HPLC (4 minute 10-90 gradient) t_(R)2.37 min; MS m/z 396.3 [M+H]⁺.

Example 161 Preparation of3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 3-[5-amino-4-(3-iodobenzoyl)-pyrazol-1-yl]-4-methylbenzoic acid

To a stirred solution of hydrazine 2 (32.5 g, 0.160 mol, 1.0 equiv) inethanol (3.6 L) was added 1 (60 g, 0.160 mol, 1.0 equiv, preparation:International Patent Application Publication No. WO 02/57101 A1, pg.84)) and triethylamine (16.56 g, 0.16 mol, 1.0 equiv) and the mixturewas heated to 65° C. All solids dissolved when temperature reached 65°C. After cooling, the solids were filtered to provide acid 3 (22 g, 30%)as a light brown solid. HPLC (Waters X-Terra 5 micron C18 column 4.6mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H₂O/acetonitrile 40/60,30 min elution) t_(R) 6.74 min, 95.2% purity;

B.3-[5-amino-4-(3-iodobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of acid 3 (21 g, 0.0469 mol, 1.0 equiv) in DMF (30ml) was added EDCI (17 g, 0.0886 mol, 2.0 equiv), HOBt (12.6 g, 0.0939,2.0 equiv) and diisopropylethylamine (24.2 g, 0.18 mol, 4.0 equiv) andthe solution was stirred for 15 minutes at room temperature whencyclopropylamine (10.7 g, 0.0939, 2.0 equiv) was added and the reactionstirred for 1 hour. The mixture was added to water and extracted withEtOAc (1 L) and washed with water (2×200 ml) and brine (200 ml), driedover anhydrous sodium sulfate and concentrated. The product was purifiedby flash chromatography on silica gel eluted with 8/2 EtOAc/hexanes toprovide the product as brown oil. The product was further purified bytrituration with Isopropyl ether (1 L) and dried under vacuum to providethe amide 4 (12 g, 50%) as an off white solid.

C.3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

To a stirred solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv) inN,N-dimethyl formamide (25 ml) under N₂ was added copper cyanide. Theresultant suspension was refluxed for 1 hour. The reaction was monitoredby TLC and checked for the completion. Heating was discontinued and thereaction mixture was cooled down to 80° C. Ice water (15 ml), 25%aqueous ammonia (15 ml), and ethyl acetate (50 ml) were added to quenchthe reaction. The mixture was filtered to remove the solids. From thefiltrate organic layer was separated. The organic layer was washed withwater, saturated brine and dried over anhydrous sodium sulfate. Solventwas removed under reduced pressure and the crude material dried at 60°C. under high vacuum then purified by column with ethyl acetate aseluent to provide the product (3 g, 51%) as an off white solid. HPLC(Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobilephase: 0.1% TEA in H₂O/acetonitrile 70/30, 30 min elution) t_(R) 23.70min, 99.4% purity; ¹H NMR (400 MHz, CDCl₃) δ8.10 (t, J=2.9 Hz, 1H), 8.06(t, J=2.7 Hz, 1H), 8.04 (m, 1H), 7.85 (t, J=2.5 Hz, 1H), 7.83 (m, 1H),7.81 (d, J=1.8 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.37 (s, 1H), 7.65 (t,J=7.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 6.41 (s, 1H), 5.94 (s, 2H), 2.88(m, 1H), 2.24 (s, 3H), 0.86 (dd, J=6.9, 6.1 Hz, 2H) 0.61 (m, 2H) ppm;¹³C NMR (400 MHz, CDCl₃) δ186.6, 167.2, 151.5, 141.3, 140.7, 140.3,135.1, 134.5, 134.0, 132.2, 131.8, 129.5, 128.7, 126.2, 118.1, 113.0,103.7, 30.9, 23.2, 17.7, 6.8 ppm.

Example 162 Preparation of3-[5-Amino-4-(3-pyrazin-2-yl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A. Preparation of3-[5-Amino-4-(3-bromobenzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of 3-bromo-1-iodobenzene (2.82 g) in THF (20 mL) at −40°C. under N₂ was added cyclohexylmagnesium chloride (2M in THF, 6 mL).The solution was kept at −40° C. to 0° C. for 20 min. then3-(5-amino-4-cyano-imidazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (0.18g) was added and the reaction was kept at rt for 1 h. Then HCl (4 M, 20mL) was added and the mixture was kept at rt for two days. The mixturewas neutralized with K₂CO₃ solution and extracted with EtOAc (2×100 mL)and the combined organics dried over Na₂SO₄, and concentrated.Purification of the crude product by column chromatography (EtOAc) gavethe desired product (0.15 g, 54%). HPLC (4 minute 10-90 gradient) t_(R)1.85 min; MS m/z 438.10, 441.07 [M+H]⁺.

B. Preparation of3-[5-Amino-4-(3-pyrazin-2-yl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A solution of3-[5-amino-4-(3-bromobenzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide(60 mg), 2-tributyltinpyrazine (120 uL) andtetrakis(triphenylphosphine)palladium(0) (30 mg) in 1,4-dioxane (0.8 mL)was heated under microwave radiation at 160° C. for 25 min. Water (3 ml)was added and the mixture was extracted with ethyl acetate (4 mL×2).Evaporation of the solvent and purification by preparatory TLC (EtOAc:MeOH=10:1) gave the desired product (38 mg, 63%). HPLC (4 minute 10-90gradient) t_(R) 2.18 min; MS m/z 439.27 [M+H]⁺.

Example 163 Preparation of3-[5-Amino-4-(3-pyrimidin-5-yl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 162 except 4-tributylstannylpyrimidinewas used in place of 2-tributylstannylpyrazine. HPLC (4 minute 10-90gradient) t_(R) 1.93 min; MS m/z 439.19 [M+H]⁺.

Example 164 Preparation of3-[5-Amino-4-(3-pyrimidin-5-yl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 162 except 2-tributylstannylpyridine wasused in place of 2-tributylstannylpyrazine. HPLC (4 minute 10-90gradient) t_(R) 2.04 min; MS m/z 438.25 [M+H]⁺.

Example 165 Preparation of3-[5-Amino-4-(3-pyrimidin-2-yl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 162 except 2-tributylstannylpyrimidinewas used in place of 2-tributylstannylpyrazine. HPLC (4 minute 10-90gradient) t_(R) 2.49 min; MS m/z 439.24 [M+H]⁺.

Example 166 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-4-methylsulfonylbenzoyl-1H-imidazole

A solution of5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-4-methylsulfonylbenzoyl-1H-imidazole(64 mg) and Oxone® (242 mg) in water/methanol (2 ml/2 ml) was reacted atroom temperature for 2 hours. The solution was evaporated and THF/MeOH(2 ml/2 ml) was added. The mixture was heated to dissolve the organicmaterials and filtered. The filtrate was concentrated under reducedpressure and the residue was purified by preparative HPLC to provide theproduct (1.6 mg). HPLC (4 minute 10-90 gradient) t_(R) 1.90 min; MS m/z439.15 [M+H]÷.

Example 167 Preparation of5-Amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-4-[3-(5-methyl)oxadiazol-3-ylbenzoly]-1H-imidazole

A mixture of N-hydroxy-3-iodobenzimidine (1.31 g), acetic anhydride (1mL) and catalytic amount of p-toluenesulfonic acid was heated in aceticacid (10 mL) at 90° C. for 6 hour. The solvent was evaporated and waterand methanol (1:1; 100 mL)) was added. The resulting precipitate wasfiltered to give the desired product (1.1 g).

To a solution 3-(3-iodophenyl)-5-methyloxadiazole (0.286 g) in THF (15ml) under N₂ was added cyclopentylmagnesiumbromide (2 M, 1.1 mL) at −20°C. The temperature was gradually raised to 5-10° C. It took about 20minutes. Then5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-4-cyanoimidazole (96mg) was added and the reaction was kept at room temperature for 0.5hour. Then diluted HCl (4M, 12 mL) was added and the reaction was heatedat 60° C. for 3 hour. After petition in water and ethyl acetate, thefinal product was purified by column chromatography (Ethylacetate/Hexane=1:1). HPLC (4 minute 10-90 gradient) t_(R) 2.03 min; MSm/z 443.20 [M+H]⁺.

Example 168 Preparation of3-(5-Amino-4-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzoyl}-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

A.3-{5-Amino-4-[3-(2-bromo-ethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methylbenzamide

To a solution of3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide(472 mg, 1.26 mmol) in THF (dry, 20 mL) at 0° C. was added of2-bromoethanol (785 mg, 6.3 mmol), PPh₃ (1.3 g, 5.04 mmol) and diethylazodicarboxylate (877 mg, 5.04 mmol) and the mixture was stirred at roomtemperature for 72 h. An aqueous solution of NH₄Cl was added then theTHF layer was isolated. The aqueous layer was extracted by EtOAc. Thecombined organic phase was washed by brine, purified by preparatoryHPLC, to provide the product as a white solid (360 mg, 59%). HPLC (4minute 10-90 gradient) t_(R) 2.72 min; MS m/z 483.14/485.09 [M+H]⁺.

B.3-(5-Amino-4-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzoyl}-pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamide

To the suspension of3-{5-amino-4-[3-(2-bromoethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide(24 mg, 0.05 mmol) in EtOH (1 ml) was added 1-methylpiperazine (100 mg,1 mmol) and the mixture was stirred at 80° C. overnight. The solvent wasremoved, residue was dissolved in EtOAc, washed by water, dried overNa₂SO₄. Solvent was removed, desired product was obtained as a colorlessoil (18 mg, 72%). HPLC (4 minute gradient) t_(R) 1.33 min; MS m/z 503.29[M+H]⁺.

Example 169 Preparation of3-[5-Amino-4-(3-{2-[bis-(2-hydroxy-ethyl)-amino]-ethoxy}-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 168 except2-[bis-(2-hydroxyethyl)-amino]-ethanol was used in place of1-methylpiperazine. HPLC (4 minute 10-90 gradient) t_(R) 1.39 min; MSm/z 508.24 [M+H]⁺.

Example 170 Preparation of3-{5-Amino-4-[3-(2-dimethylamino-ethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 168 except 2-dimethylaminoethanol wasused in place of 1-methylpiperazine. HPLC (4 minute 10-90 gradient)t_(R) 1.59 min; MS m/z 448.22 [M+H]⁺.

Example 171 Preparation of3-[5-Amino-4-[3-(2,3-dihydroxy-propoxy)-benzoyl]-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A.3-{5-Amino-4-[3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide(75 mg, 0.2 mmol) and 4-chloromethyl-2,2-dimethyl-[1,3]dioxolane (36 mg,0.24 mmol) were dissolved in DMF (4 ml) was added K₂CO₃ and the mixturestirred at 150° C. for 2 h in microwave oven. The solvent was removed,residue was dissolved in EtOAc, washed by water, brine, dried overNa₂SO₄, and concentrated. The residue was purified by columnchromatography (EtOAc:Hex=3:1) and the product was obtained as acolorless oil (18 mg, 18%). HPLC (4 minute gradient) t_(R) 2.57 min; MSm/z 491.11 [M+H]⁺.

B.3-{5-Amino-4-[3-(2,3-dihydroxy-propoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methylbenzamide

Compound 171A (10 mg) was dissolved in HOAc (1 ml), 0.5 ml water wasadded, and the mixture was stirred at 50° C. overnight. The solvent wasremoved and the residue was purified by preparative TLC (EtOAc), toprovide the product as a light yellow oil (4.1 mg, 45%). HPLC (4 minute10-90 gradient) t_(R) 1.73 min; MS m/z 451.21 [M+H]⁺.

Example 172 Preparation of3-(5-Amino-4-{3-[2-(4-chloro-phenoxy)-ethoxy]-benzoyl}-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-{5-amino-4-[3-(2-bromoethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide(24 mg, 0.05 mmol) and 4-chlorophenol (128 mg, 1 mmol) in DMF (1 mL),was added K₂CO₃ (138 mg, 1 mmol) and the mixture was stirred at 100° C.for 2 h. The mixture was cooled and the solids were filtered off. Thefiltrated was concentrated and purified by preparatory HPLC, to providethe product as a beige solid (10 mg, 38%). HPLC (4 minute 10-90gradient) t_(R) 2.77 min; MS m/z 531.21 [M+H]⁺.

Example 173 Preparation of3-{5-Amino-4-[3-(4H-[1,2,4]triazol-3-yl)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

To a stirred solution of3-[5-amino-4-(3-carbamoyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide(120 mg) in DMF (2 mL), was added N,N-dimethylformamide dimethyl acetal(5 ml) and the solution was stirred at 80° C. overnight. The solvent wasremoved, residue was dissolved in AcOH (5 ml), hydrazine monohydrate (3ml) was added and the mixture stirred at 90° C. overnight. The solutionwas acidified with hydrochloric acid to pH ˜1 and stirred at 80° C.overnight. The solvent was removed and the residue was resuspended inEtOAc, then washed by aqueous K₂CO₃ solution, water, and brine, andconcentrated. The crude product was purified by column chromatography onsilica gel eluted with EtOAc to provide product as a white solid (65 mg,51%). HPLC (4 minute 10-90 gradient) t_(R) 1.58 min; MS m/z 428.18[M+H]⁺.

Example 174 Preparation of3-{5-Amino-4-[3-(4H-[1,2,4]triazol-3-yl)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide

Similar procedure as in Example 173 except3-[5-amino-4-(3-carbamoyl-benzoyl)-imidazol-1-yl]-N-cyclopropyl-4-methyl-benzamidewas used in place of3-[5-amino-4-(3-carbamoyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide.HPLC (4 minute 10-90 gradient) t_(R) 1.58 min; MS m/z 428.24 [M+H]⁺.

Example 175 Preparation of{5-Amino-1-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-1H-pyrazol-4-yl}-phenyl-methanone

A.N-[3-(5-Amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoyl]-hydrazinecarboxylicacid tert-butyl ester

To DMF (10 mL) at rt was added3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid 1 (0.50 g, 1.56mmol, 1.0 eq), t-butylcarbazate (0.206 g, 1.56 mmol, 1.0 eq), EDCI(0.313 g, 1.63 mmol, 1.05 eq) and HOBt (0.238 g, 1.56 mmol, 1.0 eq). Thereaction was stirred for 19 h, poured into brine (100 mL) and extractedwith EtOAc (2×20 mL). The organic extracts were combined were washedwith brine (1×20 mL). The brine layer was separated and extracted withEtOAc (1×10 mL). All organic extracts were combined dried over Na₂SO₄,filtered and concentrated in vacuo. This material was dissolved inCH₂Cl₂ (10 mL) and cooled to 0° C. TFA (3 mL) was added and the reactionmixture allowed to warm to rt over 2 h. The solvent was removed in vacuoto give crude solid which was triturated with EtOAc/ether (1/1) giving 2(180 mg, 26%) as a light tan in color solid.

B.{5-Amino-1-[(2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-1H-pyrazol-4-yl}-phenyl-methanone

2 (50 mg, 0.15 mmol, 1.0 eq) was added to trimethylorthoacetate (3 ml)and heated to 140° C. in a microwaved closed container for 20 minutes.Solvent was removed in vacuo and redissolved in trimethylorthoacetate (4mL) and again heated to 140° C. for 20 minutes. The solvent was removedin vacuo and the material was dissolved in DMF and heated to 230° C. for10 minutes. The material was purified by flash chromatography (silicagel, EtOAc/hexanes 80/20) to give 3 (5.8 mg): MS m/z 360 [M+H]⁺

Example 176

The ability of the compounds provided herein to inhibit the synthesis orthe activity of cytokines can be demonstrated using the following invitro assays.

Generation of p38 Kinases

cDNAs of human p38α and β were cloned by PCR. The α and β cDNAs weresubcloned into DEST2 plasmid (Gateway, InVitrogen). His₆-p38 fusionprotein was expressed in E. coli and purified from bacterial lysates byaffinity chromatography using Ni⁺²-NTA-agarose. His₆-p38 protein wasactivated by incubating with constitutively active MKK6. Active p38 wasseparated from MKK6 by affinity chromatography. Constitutively activeMKK6 was generated in a manner similar to Raingeaud et al. [Mol. Cell.Biol., 1247-1255 (1996)].

TNF-α Production by LPS-Stimulated PBMCs

Heparinized human whole blood was obtained from healthy volunteers.Peripheral blood mononuclear cells (PBMCs) were purified from humanwhole blood by Accu-paque density gradient centrifugation andresuspended at a concentration of 5×10⁶/ml in assay medium (RPMI mediumcontaining 10% fetal bovine serum). 175 μL of cell suspension wasincubated with 10 μL of test compound (in 4% DMSO) in 96-well tissueculture plates for 30 minutes at RT. 15 μL of LPS (13.33 ug/ml stock)was then added to the cell suspension and the plate was incubated for 18hours at 37° C. in a humidified atmosphere containing 5% CO₂. Followingincubation, the culture medium was collected and stored at −20° C.

THP-1 cells (TIB-202, ATCC) were washed and resuspended at aconcentration of 1×10⁵/ml in assay medium (RPMI medium containing 3%fetal bovine serum). 175 μL of cell suspension was incubated with 10 μLof test compound (in 4% DMSO) in 96-well tissue culture plates for 30minutes at RT. 15 μL of LPS (13.33 ug/ml stock) was then added to thecell suspension and the plate was incubated for 18 hours at 37° C. in ahumidified atmosphere containing 5% CO₂. Following incubation, theculture medium was collected and stored at −20° C.

TNF-α concentration in the medium was quantified using a standard ELISAkit (BioSource International, Camarillo, Calif.). Concentrations ofTNF-α and IC₅₀ values for test compounds (concentration of compound thatinhibited LPS-stimulated TNF-α production by 50%) were calculated byfour parameter logistic curve (SigmaPlot, SPSS, Inc.).

p38α Assay

The p38α assay employed is based on measurement of ADP released in thereaction of interest through NADH oxidation obtained by coupling withpyruvate kinase and lactate dehydrogenase reactions. The assays wereperformed in 384-well UV-plates. The final volume was 25 μL preparedfrom the addition of 2.5 μL compound dissolved in 10% DMSO, 17.5 μL ofassay buffer and 5 μL of ATP. Assay buffer contains the followingreagents to give final concentration in the assay: 25 mM HEPES, 20 mM2-glycerophosphate, pH 7.6, 10 mM MgCl₂, 0.1 mM sodium orthovanadate,0.5 mM phosphoenolpyruvate, 0.12 mM NADH, 3.1 mg/ml LDH, 6.67 mg/mlpyruvate kinase, 0.25 mM peptide substrate, 2 mM DTT, 0.005% Tween 80and 20 nM p38α kinase from Upstate. Test compounds are preincubated withp38α kinase for 60 min and the reaction started by addition of ATP to0.15 mM final concentration. Reaction rates were measured at 340 nmusing SpectraMax plate-reading spectrophotometer for 10 min at 37° C.Inhibition data were analyzed by non-linear least-squares regressionusing SigmaPlot.

TNF-α Production by LPS-Stimulated Mice

Mice (Balb/c female, 6-8 weeks of age, Taconic Labs; n=8/treatmentgroup) were injected intraperitoneally with lipopolysaccharide (LPS) (50ug/kg of E. coli strain 0111:B4, Sigma) suspended in sterile saline.Ninety minutes later, mice were sedated by CO₂:O₂ inhalation and a bloodsample was obtained. Serum was separated and analyzed for TNF-αconcentrations by commercial ELISA assay per the manufacturer'sinstructions (BioSource International). Test compounds were administeredorally at various times before LPS injection. The compounds were dosedeither as suspensions or as solutions in various vehicles orsolubilizing agents.

Results

The compounds exemplified herein all showed activity in the above assaysas inhibitors of p38 kinase. The p38 inhibitory activity of certaincompounds provided herein are shown in the Table below. For p38 kinaseIC₅₀ values, “+++” represents <1 μM, “++” represents between 1.0 and 10μM and “+” represents >10 μM.

Example p38α IC₅₀ 1 +++ 2 +++ 3 ++ 4 +++ 5 ++ 6 +++ 7 +++ 8 +++ 9 +++ 10+++ 18 +++ 29 +++ 30 +++ 33 +++ 34 +++ 48 +++ 49 +++ 50 +++ 52 +++ 53+++ 76 +++ 87 +++ 128 +++ 129 +++ 135 +++ 148 +++ 171 +++

Since modifications will be apparent to those of skill in the art, theclaimed subject matter is intended to be limited only by the scope ofthe appended claims.

What is claimed is:
 1. A method of treating or ameliorating cardiacreperfusion injury, comprising administering to a subject in needthereof a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen,acyl or —P(O)(OH)₂; R² is hydrogen, halo, alkyl, or alkylthio; G isphenyl substituted with R³ and R⁴; B is phenyl; C is a pyrazole orimidazole; D is C(O)NH(cyclopropyl); R³ is selected from the groupconsisting of: (a) amino, alkylamino or dialkylamino; (b) acylamino; (c)optionally substituted phenyl or naphthyl; (d) heteroalkylcarbonyl; (e)—Y-(alkylene)-R⁹ where: Y is a single bond, —O—, —NH— or —S(O)_(n)—(where n is an integer from 0 to 2); and R⁹ is halo, cyano, optionallysubstituted phenyl, —COOH, —COR¹⁰, —COOR¹¹, —CONR¹²R¹³, —SO₂R¹⁴,—SO₂NR¹⁵R¹⁶, —NHSO₂R¹⁷ or —NHSO₂NR¹⁸R¹⁹, where R¹⁰ is alkyl, R¹¹ isalkyl, and R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ are, independentlyof each other, hydrogen or alkyl; (f) —CONR²⁵R²⁶ where R²⁵ and R²⁶independently represent hydrogen, alkyl, heteroalkyl, or R²⁵ and R²⁶together with the nitrogen to which they are attached form an optionallysubstituted heterocyclyl ring; (g) —S(O)_(n)R²⁷ where n is an integerfrom 0 to 2, and R²⁷ is alkyl, heteroalkyl, or —NR²⁸R²⁹ where R²⁸ andR²⁹ are, independently of each other, hydrogen, alkyl or heteroalkyl;(h) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl, alloptionally substituted with alkyl, halo, hydroxy or amino; (i)Z-alkylene-NR³⁰R³¹ or Z-alkylene-OR³² where Z is —NH—, —N(lower alkyl)-or —O—, and R³⁰, R³¹ and R³² are independently of each other, hydrogen,alkyl or heteroalkyl; (j) —OC(O)-alkylene-CO₂H or —OC(O)—NR′R″ where R′and R″ are independently hydrogen or alkyl; (k) hydrogen; (l) halo; (m)cyano; (n) hydroxy; (o) optionally substituted alkoxy; (p) C(L)R⁴⁰,where L is O; R⁴⁰ is hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted phenyl, optionally substituted cycloalkyl, C(L)R⁵⁶, halo,OR⁵⁵, SR⁵⁵, NR⁵⁷R⁵⁸ or SiR⁵²R⁵³R⁵⁴; where R⁵², R⁵³ and R⁵⁴ are selectedas in (i) or (ii) as follows (i) R⁵², R⁵³ and R⁵⁴ are each independentlyhydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR⁵⁵ or NR⁶²R⁶³;or (ii) any two of R⁵², R⁵³ and R⁵⁴ together form alkylene, alkenylene,alkynylene, heteroalkylene; and the other is selected as in (i); R⁵⁵ ishydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl; R⁵⁶ ishydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR⁵⁵ or NR⁶⁴R⁶⁵;where R⁶⁴ and R⁶⁵ are each independently hydrogen, alkyl, alkenyl,alkynyl, phenyl, cycloalkyl, OR⁶⁶ or NR⁶²R⁶³, or R⁶⁴ and R⁶⁵ togetherform alkylene, alkenylene, alkynylene, heteroalkylene, where R⁶⁶ ishydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl; R⁵⁷ and R⁵⁸ areselected as in (i) or (ii) as follows (i) R⁵⁷ and R⁵⁸ are eachindependently hydrogen, optionally substituted alkyl, alkenyl, alkynyl,phenyl, cycloalkyl, OR⁵⁵, NR⁶⁷R⁶⁸ or C(L)R⁶⁹, where R⁶⁷ and R⁶⁸ are eachindependently hydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl,or together form alkylene, alkenylene, alkynylene, heteroalkylene; andR⁶⁹ is hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR⁷⁰ orNR⁶²R⁶³, where R⁷⁰ is alkyl, alkenyl, alkynyl, phenyl or cycloalkyl; or(ii) R⁵⁷ and R⁵⁸ together form alkylene, alkenylene, alkynylene,heteroalkylene, or alkylenoxyalkylene; R⁶² and R⁶³ are eachindependently hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, orR⁶² and R⁶³ together form alkylene, alkenylene, alkynylene,heteroalkylene; and (q) optionally substituted alkyl; R⁴ is selectedfrom the group consisting of: (a) hydrogen; (b) halo; (c) alkyl; (d)alkoxy; and (e) hydroxy; R⁵ is selected from the group consisting of (a)hydrogen; (b) halo; and (c) alkyl; R⁶ is selected from the groupconsisting of: (a) hydrogen; (b) halo; (c) alkyl; and (d) alkoxy.
 2. Themethod according to claim 1, where C is an imidazole ring.
 3. The methodaccording to claim 1, where C is a pyrazole ring.
 4. The methodaccording to claim 1, wherein the compound is a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl; and the hydrogen of the ring NH group may be replaced by one ofthe —C(O)-A(R³)(R⁴), —R², or —B(D)(R⁶)(R⁵) substituents, wherein Arefers to the ring A and B refers to ring B in Formula II.
 5. The methodaccording to claim 1, wherein the compound is a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl.
 6. The method according to claim 1, wherein the compound is acompound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl.
 7. The method according to claim 1, wherein the compound is acompound of formula V:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl.
 8. The method according to claim 1, wherein the compound is acompound of formula Va:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl.
 9. The method according to claim 1, wherein the compound is acompound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl; and the hydrogen of the ring NH group may be replaced by one ofthe —C(O)-A(R³)(R⁴), —R², or —B(D)(R⁶)(R⁵) substituents, wherein Arefers to the ring A and B refers to ring B in Formula II.
 10. Themethod according to claim 1, wherein the compound is a compound offormula VII:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl.
 11. The method according to claim 1, wherein the compound is acompound of formula VIII:

or a pharmaceutically acceptable salt thereof, wherein the A ring isphenyl.
 12. The method of claim 1, wherein the compound is selected fromthe group consisting of:3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamide;3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;3-[5-amino-4-(3-cyano-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide;or a pharmaceutically acceptable salt thereof.
 13. The method of claim12, wherein the compound is3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide, ora pharmaceutically acceptable salt thereof.
 14. The method of claim 12,wherein the compound is3-[5-amino-4-(3-cyanobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamideor a pharmaceutically acceptable salt thereof.